Tricyclic amide and urea compounds useful for inhibition of G-protein function and for treatment of proliferative diseases

ABSTRACT

A method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells is disclosed. The method comprises the administration of a compound of Formula 1.0: ##STR1## to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammal such as a human being. Novel compounds of formulas 5.0, 5.1 and 5.2, wherein R is --C(R 20 )(R 21 )(R 46 ), and 5.3, 5.3A and 5.3B, wherein R is --N(R 25 )(R 48 ), are disclosed. Also disclosed are processes for making 3-substituted compounds of Formulas 5.0, 5.1, 5.2 and 5.3. Further disclosed are novel compounds which are intermediates in the process for making 3-substituted compounds of Formulas 5.0, 5.1, 5.2 and 5.3.

This is a continuation of application Ser. No. 08/410,187, filed Mar.24, 1995, which in turn is a continuation-in-part of U.S. applicationSer. No. 08/312,028, filed Sep. 26, 1994 (now abandoned), which in turnis a continuation-in-part of U.S. Ser. No. 08/137,862, filed Oct. 15,1993 (now abandoned).

BACKGROUND

International Publication Number WO92/11034, published Jul. 9, 1992,discloses a method of increasing the sensitivity of a tumor to anantineoplastic agent, which tumor is resistant to the antineoplasticagent, by the concurrent administration of the antineoplastic agent anda potentiating agent of the formula: ##STR2## wherein the dotted linerepresents an optional double bond, X' is hydrogen or halo, and Y' ishydrogen, substituted carboxylate or substituted sulfonyl. For example,Y' can be, amongst others, --COOR' wherein R' is C1 to C6 alkyl orsubstituted alkyl, phenyl, substituted phenyl, C7 to C12 aralkyl orsubstituted aralkyl or -2, -3, or -4 piperidyl or N-substitutedpiperidyl. Y' can also be, amongst others, SO₂ R' wherein R' is C1 to C6alkyl, phenyl, substituted phenyl, C7 to C12 aralkyl or substitutedaralkyl. Examples of such potentiating agents include11-(4-piperidylidene)-5H-benzo 5,6!cyclohepta 1,2-b!pyridines such asLoratadine.

Oncogenes frequently encode protein components of signal transductionpathways which lead to stimulation of cell growth and mitogenesis.Oncogene expression in cultured cells leads to cellular transformation,characterized by the ability of cells to grow in soft agar and thegrowth of cells as dense foci lacking the contact inhibition exhibitedby non-transformed cells. Mutation and/or overexpression of certainoncogenes is frequently associated with human cancer.

To acquire transforming potential, the precursor of the Ras oncoproteinmust undergo farnesylation of the cysteine residue located in acarboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyzesthis modification, farnesyl protein transferase, have therefore beensuggested as anticancer agents for tumors in which Ras contributes totransformation. Mutated, oncogenic forms of ras are frequently found inmany human cancers, most notably in more than 50% of colon andpancreatic carcinomas (Kohl et al., Science, Vol. 260, 1834 to 1837,1993).

In view of the current interest in inhibitors of farnesyl proteintransferase, a welcome contribution to the art would be compounds usefulfor the inhibition of farnesyl protein transferase. Such a contributionis provided by this invention.

SUMMARY OF THE INVENTION

Inhibition of farnesyl protein transferase by tricyclic compounds ofthis invention has not been reported previously. Thus, this inventionprovides a method for inhibiting farnesyl protein transferase usingtricyclic compounds of this invention which: (i) potently inhibitfarnesyl protein transferase, but not geranylgeranyl protein transferaseI, in vitro; (ii) block the phenotypic change induced by a form oftransforming Ras which is a farnesyl acceptor but not by a form oftransforming Ras engineered to be a geranylgeranyl acceptor; (iii) blockintracellular processing of Ras which is a farnesyl acceptor but not ofRas engineered to be a geranylgeranyl acceptor; and (iv) block abnormalcell growth in culture induced by transforming Ras. Several compounds ofthis invention have been demonstrated to have anti-tumor activity inanimal models.

This invention provides a method for inhibiting the abnormal growth ofcells, including transformed cells, by administering an effective amountof a compound of this invention. Abnormal growth of cells refers to cellgrowth independent of normal regulatory mechanisms (e.g., loss ofcontact inhibition). This includes the abnormal growth of: (1) tumorcells (tumors) expressing an activated Ras oncogene; (2) tumor cells inwhich the Ras protein is activated as a result of oncogenic mutation inanother gene; and (3) benign and malignant cells of other proliferativediseases in which aberrant Ras activation occurs.

Compounds useful in the claimed methods are represented by Formula 1.0:##STR3## or a pharmaceutically acceptable salt or solvate thereof,wherein: one of a, b, c and d represents N or NR⁹ wherein R⁹ is O⁻,--CH₃ or --(CH₂)_(n) CO₂ H wherein n is 1 to 3, and the remaining a, b,c and d groups represent CR¹ or CR² ; or

each of a, b, c, and d are independently selected from CR¹ or CR² ;

each R¹ and each R² is independently selected from H, halo, --CF₃,--OR¹⁰ (e.g., --OCH₃), --COR¹⁰, --SR¹⁰ (e.g., --SCH₃ and --SCH₂ C₆ H₅),--S(O)_(t) R¹¹ (wherein t is 0, 1 or 2, e.g., --SOCH₃ and --SO₂ CH₃),--SCN, --N(R¹⁰)₂, --NR¹⁰ R¹¹, --NO₂, --OC(O)R¹⁰, --CO₂ R¹⁰, --OCO₂ R¹¹,--CN, --NHC(O)R¹⁰, --NHSO₂ R¹⁰, --CONHR¹⁰, --CONHCH₂ CH₂ OH, --NR¹⁰COOR¹¹, ##STR4## --SR¹¹ C(O)OR¹¹ (e.g., --SCH₂ CO₂ CH₃), --SR¹¹ N(R⁷⁵)₂wherein each R⁷⁵ is independently selected from H and --C(O)OR¹¹ (e.g.,--S(CH₂)₂ NHC(O)O-t-butyl and --S(CH₂)₂ NH₂), benzotriazol-1-yloxy,tetrazol-5-ylthio, or substituted tetrazol-5-ylthio (e.g., alkylsubstituted tetrazol5-ylthio such as 1-methyl-tetrazol-5-ylthio),alkynyl, alkenyl or alkyl, said alkyl or alkenyl group optionally beingsubstituted with halo, --OR¹⁰ or --CO₂ R¹⁰ ;

R³ and R⁴ are the same or different and each independently represents H,any of the substituents of R¹ and R², or R³ and R⁴ taken togetherrepresent a saturated or unsaturated C₅ -C₇ fused ring to the benzenering (Ring III);

R⁵, R⁶, R⁷ and R⁸ each independently represents H, --CF₃, --COR¹⁰, alkylor aryl, said alkyl or aryl optionally being substituted with --OR¹⁰,--SR¹⁰, --S(O)_(t) R¹¹, --NR¹⁰ COOR¹¹, --N(R¹⁰)₂, --NO₂, --COR¹⁰,--OCOR¹⁰, --OCO₂ R¹¹, --CO₂ R¹⁰, OPO₃ R¹⁰ or one of R⁵, R⁶, R⁷ and R⁸can be taken in combination with R⁴⁰ as defined below to represent--(CH₂)_(r) -- wherein r is 1 to 4 which can be substituted with loweralkyl, lower alkoxy, --CF₃ or aryl, or R⁵ is combined with R⁶ torepresent ═O or ═S and/or R⁷ is combined with R⁸ to represent ═O or ═S;

R¹⁰ represents H, alkyl, aryl, or aralkyl (e.g., benzyl);

R¹¹ represents alkyl or aryl;

X represents N, CH or C, which C may contain an optional double bond(represented by the dotted line) to carbon atom 11;

the dotted line between carbon atoms 5 and 6 represents an optionaldouble bond, such that when a double bond is present, A and Bindependently represent --R¹⁰, halo, --OR¹¹ , --OCO₂ R¹¹ or --OC(O)R¹⁰,and when no double bond is present between carbon atoms 5 and 6, A and Beach independently represent H₂, --(OR¹¹)₂ ; H and halo, dihalo, alkyland H, (alkyl)₂, --H and --OC(O)R¹⁰, H and --OR¹⁰, ═O, aryl and H,═NOR¹⁰ or --O--(CH₂)_(p) --O-- wherein p is 2, 3 or 4;

R represents R⁴⁰, R⁴², R⁴⁴, or R⁵⁴, as defined below;

R⁴⁰ represents H, aryl, alkyl, cycloalkyl, alkenyl, alkynyl or --Dwherein --D represents ##STR5## wherein R³ and R⁴ are as previouslydefined and W is O, S or NR¹⁰ wherein R¹⁰ is as defined above; said R⁴⁰cycloalkyl, alkenyl and alkynyl groups being optionally substituted withfrom 1-3 groups selected from halo, --CON(R¹⁰)₂, aryl, --CO₂ R¹⁰,--OR¹², --SR¹², --N(R¹⁰)₂, --N(R¹⁰)CO₂ R¹¹, --COR¹², --NO₂ or D, wherein--D, R¹⁰ and R¹¹ are as defined above and R¹² represents R¹⁰,--(CH₂)_(m) OR¹⁰ or --(CH₂)_(q) CO₂ R¹⁰ wherein R¹⁰ is as previouslydefined, m is 1 to 4 and q is 0 to 4; said alkenyl and alkynyl R⁴⁰groups not containing --OH, --SH or --N(R¹⁰)₂ on a carbon containing adouble or triple bond respectively; or

R⁴⁰ represents phenyl substituted with a group selected from --SO₂ NH₂,--NHSO₂ CH₃, --SO₂ NHCH₃, --SO₂ CH₃, --SOCH₃, --SCH₃, or --NHSO₂ CF₃,preferably, said group is located in the para (p-) position of thephenyl ring; or

R⁴⁰ represents a group selected from ##STR6## wherein R²⁰, R²¹ and R⁴⁶are each independently selected from the group consisting of:

(1) H;

(2) --(CH₂)_(q) SC(O)CH₃ wherein q is 1 to 3 (e.g., --CH₂ SC(O)CH₃);

(3) --(CH₂)_(q) OSO₂ CH₃ wherein q is 1 to 3 (e.g., --CH₂ OSO₂ CH₃);

(4) --OH;

(5) --CS(CH₂)_(w) (substituted phenyl) wherein w is 1 to 3 and thesubstitutents on said substituted phenyl group are the samesubstitutents as described below for said substituted phenyl (e.g.,--C--S--CH₂ -4-methoxyphenyl);

(6) --NH₂ ;

(7) --NHCBZ (wherein CBZ stands for carbonylbenzyloxy--i.e., CBZrepresents --C(O)OCH₂ C₆ H₅);

(8) --NHC(O)OR²² wherein R²² is an alkyl group having from 1 to 5 carbonatoms (e.g., R²² is t-butyl thus forming --NHBOC wherein BOC stands fortert-butyloxycarbonyl--i.e., BOC represents --C(O)OC(CH₃)₃), or R²²represents phenyl substituted with 1 to 3 alkyl groups (e.g.,4-methylphenyl);

(9) alkyl (e.g., ethyl);

(10) --(CH₂)_(k) phenyl wherein k is 1 to 6, usually 1 to 4 andpreferably 1 (e.g., benzyl);

(11) phenyl;

(12) substituted phenyl (i.e., phenyl substituted with from 1 to 3substituents, preferably one) wherein the substituents are selected fromthe group consisting of: halo (e.g., Br, Cl, or I, with Br beingpreferred); NO₂ ; --OH; --OCH₃ ; --NH₂ ; --NHR²² ; --N(R²²)₂ ; alkyl(e.g., alkyl having from 1 to 3 carbons with methyl being preferred);--O(CH₂)_(t) phenyl (wherein t is from 1 to 3 with 1 being preferred);and --O(CH₂)_(t) substituted phenyl (wherein t is from 1 to 3 with 1being preferred); examples of substituted phenyls include, but are notlimited to, p-bromophenyl, m-nitrophenyl, o-nitrophenyl,m-hydroxy-phenyl, o-hydroxyphenyl, methoxyphenyl, p-methylphenyl,m-methyl-phenyl, and --OCH₂ C₆ H₅ ;

(13) naphthyl;

(14) substituted naphthyl, wherein the substituents are as defined forsubstituted phenyl above;

(15) bridged polycyclic hydrocarbons having from 5 to 10 carbon atoms(e.g., adamantyl and norbornyl);

(16) cycloalkyl having from 5 to 7 carbon atoms (e.g., cyclopentyl, andcyclohexyl);

(17) heteroaryl (e.g., pyridyl, and pyridyl N-oxide);

(18) hydroxyalkyl (e.g., --(CH₂)_(v) OH wherein v is 1 to 3, such as,for example, --CH₂ OH);

(19) substituted pyridyl or substituted pyridyl N-oxide wherein thesubstituents are selected from methylpyridyl, morpholinyl, imidazolyl,1-piperidinyl, 1-(4-methylpiperazinyl), --S(O)_(t) R¹¹, or any of thesubstituents given above for said substituted phenyl, and saidsubstitutents are bound to a ring carbon by replacement of the hydrogenbound to said carbon; ##STR7## (23) --NHC(O)--(CH₂)_(k) -phenyl or--NH(O)--(CH₂)_(k) -substituted phenyl, wherein said k is as definedabove (i.e., 1-6, usually 1-4 and preferably 1);

(24) piperidine Ring V: ##STR8## wherein R⁵⁰ represents H, alkyl (e.g.,methyl), alkylcarbonyl (e.g., CH₃ C(O)--), alkyloxycarbonyl (e.g.,--C(O)O-t-C₄ H₉, --C(O)OC₂ H₅, and --C(O)OCH₃), haloalkyl (e.g.,trifluromethyl), or --C(O)NH(R¹⁰) wherein R¹⁰ is H or alkyl; Ring Vincludes ##STR9## examples of Ring V include: ##STR10## (25) --NHC(O)CH₂C₆ H₅ or --NHC(O)CH₂ -substituted-C₆ H₅, for example --NHC(O)CH₂-p-hydroxyphenyl, --NHC(O)CH₂ -m-hydroxyphenyl, and --NHC(O)CH₂-o-hydroxyphenyl;

(26) --NHC(O)OC₆ H₅ ; ##STR11## (30) --OC(O)-heteroaryl, for example##STR12## (31) --O-alkyl (e.g., --OCH₃); (32) --CF₃ ;

(33) --CN;

(34) a heterocycloalkyl group of the formula ##STR13## and (35) apiperidinyl group of the formula ##STR14## wherein R⁸⁵ is H, alkyl, oralkyl substituted by --OH or --SCH₃ ; or

R²⁰ and R²¹ taken together form a ═O group and the remaining R⁴⁶ is asdefined above; or

Two of R²⁰, R²¹ and R⁴⁶ taken together form piperidine Ring V ##STR15##wherein R⁵⁰ represents H, alkyl (e.g., methyl), alkylcarbonyl (e.g., CH₃C(O)--), alkyloxycarbonyl (e.g., --C(O)O-t-C₄ H₉, --C(O)OC₂ H₅, and--C(O)OCH₃), haloalkyl (e.g., trifluro-methyl), or --C(O)NH(R¹⁰) whereinR¹⁰ is H or alkyl; Ring V includes ##STR16## examples of Ring V include:##STR17## with the proviso R⁴⁶, R²⁰, and R²¹ are selected such that thecarbon atom to which they are bound does not contain more than oneheteroatom (i.e., R⁴⁶, R²⁰, and R²¹ are selected such that the carbonatom to which they are bound contains 0 or 1 heteroatom);

R⁴⁴ represents ##STR18## wherein R²⁵ represents heteroaryl (e.g.,pyridyl or pyridyl N-oxide), N-methylpiperidinyl or aryl (e.g., phenyland substituted phenyl); and R⁴⁸ represents H or alkyl (e.g., methyl);

R⁵⁴ represents an N-oxide heterocyclic group of the formula (i), (ii),(iii) or (iv): ##STR19## wherein R⁵⁶, R⁵⁸, and R⁶⁰ are the same ordifferent and each is independently selected from H, halo, --CF₃,--OR¹⁰, --C(O)R¹⁰, --SR¹⁰, --S(O)_(e) R¹¹ (wherein e is 1 or 2),--N(R¹⁰)₂, --NO₂, --CO₂ R¹⁰, --OCO₂ R¹¹, --OCOR¹⁰, alkyl, aryl, alkenylor alkynyl, which alkyl may be substituted with --OR¹⁰, --SR¹⁰ or--N(R¹⁰)₂ and which alkenyl may be substituted with OR¹¹ or SR¹¹ ; or

R⁵⁴ represents an N-oxide heterocyclic group of the formula (ia), (iia),(iiia) or (iva): ##STR20## wherein Y represents N⁺ -O⁻ and E representsN; or R⁵⁴ represents an alkyl group substituted with one of said N-oxideheterocyclic groups (i), (ii), (iii), (iv), (ia), (iia), (iiia) or(iva);

Z represents O or S such that R can be taken in combination with R⁵, R⁶,R⁷ or R⁸ as defined above, or R represents R⁴⁰, R⁴², R⁴⁴ or R⁵⁴.

Examples of R²⁰, R²¹, and R⁴⁶ for the above formulas include: ##STR21##

Examples of R²⁵ groups include: ##STR22## wherein Y represents N or NO,R²⁸ is selected from the group consisting of: C₁ to C₄ alkyl, halo,hydroxy, NO₂, amino (--NH₂), --NHR³⁰, and --N(R³⁰)₂ wherein R³⁰represents C₁ to C₆ alkyl.

Tricyclic compounds useful in the methods of this invention aredescribed in: (1) U.S. Pat. No. 5,151,423; (2) U.S. Pat. No. 4,826,853;(3) U.S. Pat. No. 5,089,496; (4) WO 88/03138 published on May 5, 1988(PCT/US87/02777); and (5) U.S. Pat. No. 5,104,876; the disclosures ofeach being incorporated herein by reference thereto. Those compoundswithin the scope of this invention which are not described in thesedocuments are described herein.

This invention also provides novel compounds of Formula 1.0 having theformula: ##STR23## wherein all substituents are as defined for Formula1.0

This invention further provides novel compounds of Formula 1.0 havingthe formula: ##STR24## wherein all substituents are as defined forFormula 1.0

Additionally, this invention provides novel compounds of Formula 1.0having the formula: ##STR25## wherein all substituents are as definedfor Formula 1.0.

Compounds of Formula 5.2 include compounds wherein the substituents R²⁰,R²¹, and R⁴⁶ are selected such that when one of said substituents R²⁰,R²¹, and R⁴⁶ (e.g., R⁴⁶) is selected from the group consisting of: (1)H, (2) --OH, (3) --NH₂, (4) --NHC(O)OR²², (5) alkyl, (6) phenyl, (7)heteroaryl, (8) hydroxyalkyl, (9) substituted pyridyl, (10) substitutedphenyl and (11) --O-alkyl, then the remaining two of said substituentsR²⁰, R²¹ and R⁴⁶ (e.g., R²⁰ and R²¹) cannot both be H when: (a) R¹ andR² are both H, and (b) the double bond between C-5 and C-6 is absent,and (c) both A and B are H₂, and (d) R⁴ is H, and (e) R³ is H or Cl atC-8. Compounds of Formula 5.2 also include compounds wherein when R⁴⁶ isa group (1) to (11) defined above then R²⁰ and R²¹ cannot both be Hwhen: R¹ and R² are both H, and both A and B are H or H₂. Compounds ofFormula 5.2 further include compounds wherein when R⁴⁶ is a group (1) to(11) defined above then R²⁰ and R²¹ cannot both be H when R¹ and R² areboth H. Compounds of Formula 5.2 also include compounds wherein two ofR²⁰, R²¹ and R⁴⁶ are not H when R¹ and R² are both H.

This invention further provides novel compounds of Formula 1.0 havingthe formula: ##STR26## wherein all the substituents are as defined forFormula 1.0. Preferably R²⁵ represents heteroaryl.

This invention also provides novel compounds of the formula 7.0 havingthe formula: ##STR27## wherein R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ areas defined above for compounds of the formula 1.0, which compounds areuseful in the methods claimed herein.

This invention also provides a method for inhibiting tumor growth byadministering an effective amount of the tricyclic compounds, describedherein, to a mammal (e.g., a human) in need of such treatment. Inparticular, this invention provides a method for inhibiting the growthof tumors expressing an activated Ras oncogene by the administration ofan effective amount of the above described compounds. Examples of tumorswhich may be inhibited include, but are not limited to, lung cancer(e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreaticcarcinoma such as, for example, exocrine pancreatic carcinoma), coloncancers (e.g., colorectal carcinomas, such as, for example, colonadenocarcinoma and colon adenoma), myeloid leukemias (for example, acutemyelogenous leukemia (AML)), thyroid follicular cancer, myelodysplasticsyndrome (MDS), bladder carcinoma and epidermal carcinoma.

It is believed that this invention also provides a method for inhibitingproliferative diseases, both benign and malignant, wherein Ras proteinsare aberrantly activated as a result of oncogenic mutation in othergenes--i.e., the Ras gene itself is not activated by mutation to anoncogenic form--with said inhibition being accomplished by theadministration of an effective amount of the tricyclic compoundsdescribed herein, to a mammal (e.g., a human) in need of such treatment.For example, the benign proliferative disorder neurofibromatosis, ortumors in which Ras is activated due to mutation or overexpression oftyrosine kinase oncogenes (e.g., neu, src, abl, lck, and fyn), may beinhibited by the tricyclic compounds described herein.

The compounds of this invention inhibit farnesyl protein transferase andthe farnesylation of the oncogene protein Ras. This invention furtherprovides a method of inhibiting ras farnesyl protein transferase, inmammals, especially humans, by the administration of an effective amountof the tricyclic compounds described above. The administration of thecompounds of this invention to patients, to inhibit farnesyl proteintransferase, is useful in the treatment of the cancers described above.

The tricyclic compounds useful in the methods of this invention inhibitthe abnormal growth of cells. Without wishing to be bound by theory, itis believed that these compounds may function through the inhibition ofG-protein function, such as ras p21, by blocking G-proteinisoprenylation, thus making them useful in the treatment ofproliferative diseases such as tumor growth and cancer. Without wishingto be bound by theory, it is believed that these compounds inhibit rasfarnesyl protein transferase, and thus show antiproliferative activityagainst ras transformed cells.

This invention also provides a process for producing 3-nitro substitutedcompounds. The process comprises reacting one molar equivalent of acompound: ##STR28## wherein R¹, R², R³, R⁴, A, B, a, b, d, and thedotted lines are as defined for Formula 1.0; and R⁶⁵ represents H or--OR⁶⁶ wherein R⁶⁶ represents alkyl (e.g., C₁ to C₄ alkyl, preferablyethyl); with one molar equivalent of a nitrating reagent, said nitratingreagent being preformed (i.e., prepared first) by mixing, at coldtemperature (e.g., at 0° C.) equimolar amounts of tetrabutyl ammoniumnitrate with TFAA; the reaction of the nitrating reagent with thecompound of Formula 1.0g taking place in a suitable aprotic solvent(e.g., CH₂ Cl₂, CHCl₃, toluene or THF); said reaction with saidnitrating reagent being conducted at a temperature and for a period oftime sufficient to allow the reaction to proceed at a reasonable rate toproduce the desired final 3-nitro compound of Formula 1.0h (describedbelow)--i.e., the reaction of the compound of Formula 1.0g with saidnitrating reagent is conducted at an intial temperature of 0° C., andsaid reaction temperature is thereafter allowed to rise to about 25° C.during the reaction time period. The reaction usually proceeds overnightto completion, i.e., the reaction usually proceeds for about 16 hours.The reaction can be conducted within a temperature of 0° C. to about 25°C. during a time period of about 10 to about 24 hours. Preferably thereaction is initially conducted at 0° C. and the temperature is allowedto warm up to 25° C. The reaction produces the 3-nitro compound (1.0h):##STR29##

The compound of Formula 1.0h can then be converted to other3-substituted products by methods well known to those skilled in theart. For example, the 3-nitro compounds can be convened to 3-amino,3-halo, 3-cyano, 3-alkyl, 3-aryl, 3-thio, 3-arylalkyl, 3-hydroxyl, and3-OR⁶⁷ wherein R⁶⁷ is alkyl or aryl. The 3-substituted compounds canthen be converted to final products (wherein R⁶⁵ is R⁴² or R⁴⁴) by theprocedures described herein.

This invention also provides a process for producing 3-nitro compoundsof the formula (1.0i): ##STR30## by producing a compound of Formula 1.0hfrom 1.0g as described above; and then hydrolyzing the compound ofFormula 1.0h by dissolving the compound of Formula 1.0h in a sufficientamount of concentrated acid (e.g., concentrated HCl or aqueous sulfuricacid), and heating the resulting mixture to a temperature sufficient toremove (hydrolyze) the --C(O)R⁶⁵ substituent, for example, heating toreflux or to a temperature of about 100° C. This hydrolysis process isexemplified in Preparative Example 28.

The compound of Formula 1.0i can then be converted to other3-substituted compounds as discussed above for the compounds of Formula1.0h. The compounds of Formula 1.0i can then be converted to compoundsof this invention by the methods described herein.

This invention also provides a process for producing compounds of theformula (1.0j): ##STR31## by reacting one molar equivalent a compound offormula (1.0k): ##STR32## with one molar equivalent of a nitratingreagent, said nitrating reagent being preformed (i.e., prepared first)by mixing, at cold temperature (e.g., at 0° C.) equimolar amounts oftetrabutyl ammonium nitrate with TFAA; the reaction of the nitratingreagent with the compound of Formula 1.0k taking place in a suitableaprotic solvent (e.g., CH₂ Cl₂, CHCl₃, toluene or THF); said reactionwith said nitrating reagent being conducted at a temperature and for aperiod of time sufficient to allow the reaction to proceed at areasonable rate to produce the desired final 3-nitro compound of Formula1.0j--i.e., the reaction of the compound of Formula 1.0k with saidnitrating reagent is conducted at an intial temperature of 0° C., andsaid reaction temperature is thereafter allowed to rise to about 25° C.during the reaction time period. The reaction usually proceeds overnightto completion, i.e., the reaction usually proceeds for about 16 hours.The reaction can be conducted within a temperature of 0° C. to about 25°C. during a time period of about 10 to about 24 hours. Preferably thereaction is initially conducted at 0° C. and the temperature is allowedto warm up to 25° C. In Formulas 1.0j and 1.0k, R¹, R², R³, R⁴, A, B, a,b, d, and the dotted lines are as defined for Formula 1.0

The compounds of Formula 1.0j can be converted to compounds of Formula1.0h by methods described below. Also, as discussed above for thecompounds of Formula 1.0h, the compounds of Formula 1.0j can beconverted to other 3-substituted compounds wherein the substituents arethose discussed above for Formula 1.0h.

The compounds of Formula 1.0j can be converted to compounds of Formula1.0m: ##STR33## wherein R⁶⁸ is H or --COOR^(a) wherein R^(a) is a C₁ toC₃ alkyl group (preferably R⁶⁸ is H), by reducing a compound of Formula1.0j with a suitable reducing agent (such as sodium borohydride) in asuitable solvent (such as EtOH or MeOH) at a suitable temperature toallow the reaction to proceed at a reasonable rate (e.g., 0° to about25° C.); reacting the resulting product (Formula 1.0j wherein the ═O hasbeen reduced to a --OH) with a chlorinating agent (e.g., thionylchloride) in an suitable organic solvent (e.g., benzene, toluene orpyridine) at a suitable temperature to allow the reaction to proceed ata reasonable rate (e.g., about -20° to about 20° C., preferably at -15°C., see, for example Preparative Example 7) to produce a compound ofFormula 1.0n: ##STR34## and reacting a compound of Formula 1.0n with acompound of the formula: ##STR35## wherein R⁶⁸ is as previously defined,and is preferably H, in a suitable organic solvent (such as THF ortoluene) containing a suitable base (such as Et₃ N orN-methylmorpholine) at a suitable temperature to allow the reaction toproceed at a reasonable rate (e.g., 25° to about 120° C.).

Compounds of Formula 1.0m can be convened to compounds of this inventionby the methods disclosed herein. Also, as discussed above for thecompounds of Formula 1.0h, the compounds of Formula 1.0m can beconverted to other 3-substituted compounds wherein the substituents arethose discussed above for Formula 1.0h.

This invention also provides novel compounds (produced in the abovedescribed processes as intermediates to the compounds of this invention)having the formulas: ##STR36## wherein all substituents are as definedherein.

Preferably, for the intermediate compounds of the processes of thisinvention, R¹ and R² are H; R³ is halo, most preferably Cl, in the C-8position; R⁴ is H; and A and B are H when the double between C-5 and C-6is present, and A and B are H₂ when the bond between C-5 and C-6 is asingle bond (most preferably the bond between C-5 and C-6 is a singlebond). Those skilled in the art will appreciate that Rings I, II, and/orIII can be further substituted, as described herein, to produce thedesired compounds of the invention.

Examples of such novel intermediate compounds include: ##STR37##

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the following terms are used as defined below unlessotherwise indicated:

M⁺ -represents the molecular ion of the molecule in the mass spectrum;

MH⁺ -represents the molecular ion plus hydrogen of the molecule in themass spectrum;

Bu-represents butyl;

Et-represents ethyl;

Me-represents methyl;

Ph-represents phenyl;

benzotriazol-1-yloxy represents ##STR38## 1-methyl-tetrazol-5-ylthiorepresents ##STR39## alkyl-(including the alkyl portions of alkoxy,alkylamino and dialkylamino)-represents straight and branched carbonchains and contains from one to twenty carbon atoms, preferably one tosix carbon atoms;

alkanediyl-represents a divalent, straight or branched hydrocarbon chainhaving from 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms, thetwo available bonds being from the same or different carbon atomsthereof, e.g., methylene, ethylene, ethylidene, --CH₂ CH₂ CH₂ --, --CH₂CHCH₃, --CHCH₂ CH₃, etc.

cycloalkyl-represents saturated carbocyclic rings branched or unbranchedof from 3 to 20 carbon atoms, preferably 3 to 7 carbon atoms;

heterocycloalkyl-represents a saturated, branched or unbranchedcarbocylic ring containing from 3 to 15 carbon atoms, preferably from 4to 6 carbon atoms, which carbocyclic ring is interrupted by 1 to 3hetero groups selected from --O--, --S-- or --NR¹⁰ -(suitableheterocycloalkyl groups including 2- or 3-tetrahydrofuranyl, 2- or3-tetrahydrothienyl, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 2-or 3-piperizinyl, 2- or 4-dioxanyl, etc.);

alkenyl-represents straight and branched carbon chains having at leastone carbon to carbon double bond and containing from 2 to 12 carbonatoms, preferably from 2 to 6 carbon atoms and most preferably from 3 to6 carbon atoms;

alkynyl-represents straight and branched carbon chains having at leastone carbon to carbon triple bond and containing from 2 to 12 carbonatoms, preferably from 2 to 6 carbon atoms;

aryl (including the aryl portion of aryloxy and aralkyl)-represents acarbocyclic group containing from 6 to 15 carbon atoms and having atleast one aromatic ring (e.g., aryl is a phenyl ring), with allavailable substitutable carbon atoms of the carbocyclic group beingintended as possible points of attachment, said carbocyclic group beingoptionally substituted (e.g., 1 to 3) with one or more of halo, alkyl,hydroxy, alkoxy, phenoxy, CF₃, amino, alkylamino, dialkylamino, --COOR¹⁰or --NO₂ ; and

halo-represents fluoro, chloro, bromo and iodo; and

heteroaryl-represents cyclic groups, optionally substituted with R³ andR⁴, having at least one heteroatom selected from O, S or N, saidheteroatom interrupting a carbocyclic ring structure and having asufficient number of delocalized pi electrons to provide aromaticcharacter, with the aromatic heterocyclic groups preferably containingfrom 2 to 14 carbon atoms, e.g., triazolyl, 2-, 3- or 4-pyridyl orpyridyl N-oxide (optionally substituted with R³ and R⁴), wherein pyridylN-oxide can be represented as: ##STR40##

The following solvents and reagents are referred to herein by theabbreviations indicated: tetrehydrofuran (THF); ethanol (EtOH); methanol(MeOH); acetic acid (HOAc or AcOH); ethyl acetate (EtOAc);N,N-dimethylformamide (DMF); trifluoroacetic acid (TFA); trifluoroaceticanhydride (TFAA); 1-hydroxybenzotriazole (HOBT); m-chloroperbenzoic acid(MCPBA); triethylamine (Et₃ N); diethyl ether (Et₂ O); ethylchloroformate (ClCO₂ Et); 1-(3-dimethylaminopropyl)-3-ethyl carbodiimdehydrochloride (DEC)

Reference to the position of the substituents R¹, R², R³, and R⁴ isbased on the numbered ring structure: ##STR41## For example, R¹ can beat the C-4 position and R² can be at the C-2 or C-3 position. Also, forexample, R³ can be at the C-8 position and R⁴ can be at the C-9position.

Representative structures of Formula 1.0 include but are not limited to:##STR42##

Preferably, for the compounds of Formula 1.0 (including 1.0a to 1.0d):

each of a, b, c, and d are C (carbon); or

one of a, b, c and d (most preferably a) represents N or NO, mostpreferably N, and the remaining a, b, c and d groups represent CR¹ orCR² ;

each R¹ and each R² is independently selected from H, halo (e.g., Cl, Brand F), --CF₃, --OR¹⁰ (e.g., hydroxy and alkoxy (e.g., --OCH₃)), alkyl(e.g., methyl and t-butyl, said alkyl group being optionally substitutedwith halo), benzotriazol-1-yloxy, --S(O)_(t) R¹¹ (e.g., --SCH₂ CH₃),--SR¹¹ C(O)OR¹¹ (e.g., --SCH₂ CO₂ CH₃), --SR¹⁰ (e.g., R¹⁰ represents--CH₂ C₆ H₅) and 1-methyl-tetrazol-5-ylthio; most preferably R¹ and R²are independently H, halo, --CF₃, lower alkyl (e.g., C₁ to C₄, morepreferably methyl) or benzotriazol-1-yloxy; more preferably R¹ is Cl orH, and R² is H, Cl or Br; still more preferably R¹ is at the C-4position, and R² is at the C-3 position; even more preferably R² is Br,Cl or I;

R³ and R⁴ are the same or different and each independently represents H,halo, --CF₃, --OR¹⁰, --COR¹⁰, --SR¹⁰, --S(O)_(t) R¹¹ (wherein t is 0, 1or 2), --N(R¹⁰)₂, --NO₂, --OC(O)R¹⁰, --CO₂ R¹⁰, --OCO₂ R¹¹, --C(O)NHR¹⁰,--CN, --NR¹⁰ COOR¹¹, alkynyl, alkenyl or alkyl, said alkyl or alkenylgroup optionally being substituted with halo, --OR¹⁰ or --CO₂ R¹⁰ ; mostpreferably R³ and R⁴ independently represent H, halo, --CF₃, --OR¹⁰ oralkyl (said alkyl group being optionally substituted with halo); morepreferably R³ and R⁴ independently represent H or halo (e.g., Cl, Br, orF); even more preferably R³ is at the C-8 position and R⁴ is at the C-9position; still more preferably R³ is Cl at the C-8 position and R⁴ is Hat the C-9 position;

R⁵, R⁶, R⁷ and R⁸ each independently represents H, --CF₃ or alkyl (saidalkyl optionally being substituted with --OR¹⁰); most preferably R⁵, R⁶,R⁷ and R⁸ independently represent H and alkyl, and more preferably H;

when the optional double bond between carbon atoms 5 and 6 is present, Aand B independently represent H, --R¹⁰ or --OR¹⁰, most preferably H,lower alkyl (C₁ to C₄) and alkyloxy (i.e., R¹⁰ represents alkyl), morepreferably H and --OH, and still more preferably H; and when no doublebond is present between carbon atoms 5 and 6, A and B each independentlyrepresent H₂, --(OR¹⁰)₂, alkyl and H, (alkyl)₂, --H and --OR¹⁰ or ═O,most preferably H₂, --H and --OH, or ═O, and more preferably Arepresents H₂ and B represents H₂ or ═O;

R represents R⁴² or R⁴⁴ ; and

Z represents O or S, and most preferably O.

Compounds of Formula 5.0 include: ##STR43##

Compounds of Formula 5.1 include: ##STR44##

Compounds of Formula 5.2 additionally include: ##STR45##

Compounds of Formula 5.3 include: ##STR46##

Compounds of Formula 5.3A include: ##STR47##

For the compounds of Formulas 5.0, 5.0a-5.0g, 5.1, 5.1a-5.1g, 5.2,5.2a-5.2b, 5.3, 5.3a-5.3g, 5.3A, 5.3Aa-5.3Ag, and 5.3B, the definitionsof the substituents are as defined for Formula 1.0.

Preferably, for compounds of Formulas 5.0, 5.0a-5.0g, 5.1, 5.1a-5.1g,5.2, and 5.2a-5.2b, R⁴⁶ is selected from piperidine Ring V, heteroaryl,phenyl, substituted phenyl, substituted pyridyl or substituted pyridylN-oxide, and R²⁰ and R²¹ are independently selected from H or alkyl.Most preferably, R⁴⁶ is pyridyl, pyridyl N-oxide or piperidine Ring V.More preferably, R⁴⁶ is pyridyl, pyridyl N-oxide or piperidine Ring Vand both R²⁰ and R²¹ are hydrogen or both R²⁰ and R²¹ are alkyl (stillmore preferably methyl).

Even more preferably, R⁴⁶ is selected from 3-pyridyl, 4-pyridyl,3-pyridyl N-oxide, 4-pyridyl N-oxide, 4-N-methylpiperidinyl,3-N-methylpiperidinyl, 4-N-acetylpiperidinyl or 3-N-acetylpiperidinyl,and both R²⁰ and R²¹ are hydrogen or both R²⁰ and R²¹ are alkyl (stilleven more preferably methyl). Even still more preferably, R⁴⁶ isselected from 3-pyridyl, 3-pyridyl N-oxide, 4-pyridyl, and 4-pyridylN-oxide, and both R²⁰ and R²¹ are hydrogen or both R²⁰ and R²¹ aremethyl.

Examples of the R⁴² groups include: ##STR48##

Preferably for the compounds of Formulas 5.3, 5.3a-5.3g, 5.3A,5.3Aa-5.3Ag, and 5.3B, R²⁵ represents phenyl, 2-pyridyl, 3-pyridyl,4-pyridyl, or 2-, 3- or 4-pyridyl N-oxide, and most preferably 4-pyridylor 4-pyridyl N-oxide. More prefereably, R⁴⁸ represents H or methyl andstill more preferably H.

Compounds of the formula 7.0c include compounds of the formula:##STR49## wherein R²¹, R²⁰, R⁴⁶, R²⁵ and R⁴⁸ are as defined above forcompounds of the formula 1.0.

Compounds of the formula 7.0b include compounds of the formula:##STR50## wherein R²¹, R²⁰, R⁴⁶, R²⁵ and R⁴⁸ are as defined above forcompounds of the formula 1.0.

Compounds of the formula 7.0a include compounds of the formula:##STR51## wherein R²¹, R²⁰, R⁴⁶, R²⁵ and R⁴⁸ are as defined above forcompounds of the formula 1.0.

Preferably for compounds of the formula 7.0e, 7.0g and 7.0j the groupR⁴⁶ is selected from piperidine ring V, heteroaryl, phenyl, substitutedphenyl, substituted pyridyl or substituted pyridyl N-oxide, and R²⁰ andR²¹ are independently selected from H or alkyl. Most preferably R ispyridyl, pyridyl N-oxide or piperidine ring V. It is also preferred thatR²⁰ and R²¹ are both H or are both alkyl, preferably methyl.

Preferably for compounds of the formula 7.0f, 7.0h and 7.0k, the groupR²⁵ is phenyl, 3-pyridyl, 4-pyridyl, 3-pyridyl N-oxide, 4-pyridylN-oxide or piperidine ring V. More preferably R⁴⁸ is H or methyl, with Hbeing most preferred.

Preferably for the compounds of formula 7.0a, 7.0b, 7.0c, 7.0e, 7.0f,7.0g, 7.0h, 7.0j and 7.0k the groups R⁵, R⁶, R⁷ and R⁸ are H, and R¹,R², R³ and R⁴ are independently selected from H, halo, --NO₂, --N(R¹⁰)₂,alkyl, alkenyl, alkynyl, --COR¹⁰, --CO₂ R¹⁰, --CF₃, --OR¹⁰, and --CN,wherein R¹⁰ is as defined above for compounds of the formula 1.0.

Representative compounds of the invention include: ##STR52##

Preferred compounds of this invention are selected from the groupconsisting of compounds of Examples: 1, 2, 3, 4, 5, 6, 19, 42, 43, 44,45, 46, 47, 48, 49, 75, 76, 78, 82, 83, 84, 85, 89, 121, 180, 182, 183,184, 187 (6.7 and 6.8), 192, 196, 197, 198, 200, 201, 206, 222, 223,224, 225, 226, 227, 233, 234, 236, 239, 246, 247, 248, 249, 250, 251,261, 262, 266, 267, 269, 273, 276, 283, 285, 286, 287, 288, 289, 291,292, 293, 299, 300, 301, 303, 307, 309, 311, 312, 313, 314, 316, 350,351, 352, 354 and 356.

More preferred compounds of this invention are selected from the groupconsisting of compounds of Examples: 1, 2, 42, 43, 75, 78, 82, 180, 183,187 (6.7 and 6.8), 196, 197, 198, 200, 222, 223, 224, 227, 233, 234,246, 247, 248, 249, 250, 251, 266, 269, 273, 283, 285, 286, 291, 292,300, 301, 303, 307, 311, 312, 313, 314, 350, 351, 352, 354 and 356.

Even more preferred compounds of this invention are selected from thegroup consisting of compounds of Examples: 82, 197, 233, 246, 266, 312,351, 352, 354 and 356.

Also more preferred are the compounds of Examples: 426, 400-G, 400-C,400-F, 400-E, 425-H, 401, 400-B, 400, 400-L, 425-U, 413, 400-J, 417-B,438, 411-W, 425-O, 400-D, 400-K, 410-G and 400-H.

Lines drawn into the ring systems indicate that the indicated bond maybe attached to any of the substitutable ring carbon atoms.

Certain compounds of the invention may exist in different isomeric(e.g., enantiomers and diastereoisomers) forms. The inventioncontemplates all such isomers both in pure form and in admixture,including racemic mixtures. Enol forms are also included.

Certain tricyclic compounds will be acidic in nature, e.g. thosecompounds which possess a carboxyl or phenolic hydroxyl group. Thesecompounds may form pharmaceutically acceptable salts. Examples of suchsalts may include sodium, potassium, calcium, aluminum, gold and silversalts. Also contemplated are salts formed with pharmaceuticallyacceptable amines such as ammonia, alkyl amines, hydroxyalkylamines,N-methylglucamine and the like.

Certain basic tricyclic compounds also form pharmaceutically acceptablesalts, e.g., acid addition salts. For example, the pyrido-nitrogen atomsmay form salts with strong acid, while compounds having basicsubstituents such as amino groups also form salts with weaker acids.Examples of suitable acids for salt formation are hydrochloric,sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic,fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineraland carboxylic acids well known to those in the art. The salts areprepared by contacting the free base form with a sufficient amount ofthe desired acid to produce a salt in the conventional manner. The freebase forms may be regenerated by treating the salt with a suitabledilute aqueous base solution such as dilute aqueous NaOH, potassiumcarbonate, ammonia and sodium bicarbonate. The free base forms differfrom their respective salt forms somewhat in certain physicalproperties, such as solubility in polar solvents, but the acid and basesalts are otherwise equivalent to their respective free base forms forpurposes of the invention.

All such acid and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Compounds of Formula 1.0 wherein R is --N(R¹⁰)₂, and compounds ofFormulas 5.3, 5.3A and 5.3B can be prepared by reacting compound 405.00(described below) with an isocyanate (R¹⁰ --N═C═O) in a solvent such asDMF, CH₂ Cl₂ or THF in accordance with methods known in the art.

The following processes may be employed to produce compounds of theinvention--i.e., compounds of Formula 1.0 represented by compounds ofFormulas 5.0, 5.1, 5.2 and 5.3. For purposes of describing theprocesses, the compounds are represented by Formula 400.00: ##STR53##wherein R represents R⁴² or R⁴⁴, and all other substitutents are asdescribed herein.

A. A compound of Formula 405.00 may be coupled with a compound of theformula RCOOH in the presence of coupling agent such as DEC,N,N'-dicyclohexylcarbodiimide (DCC) or N,N'-carbonyldiimidazole (CDI) toproduce compounds of Formula 400.00: ##STR54## The reaction is usuallyconducted in an inert solvent such as THF, DMF or CH₂ Cl₂ at atemperature between about 0° C. and reflux, preferably at about roomtemperature. When the coupling agent is DCC or DEC, the reaction ispreferably run in the presence of HOBT. Method A is the method of choicefor preparing compounds of this invention.

B. A compound of Formula 405.00 may also be reacted with a compound ofFormula 410.00 in the presence of base to produce compounds of Formula400.00: ##STR55##

Representative examples of appropriate bases are pyridine and Et₃ N. Ldesignates a suitable leaving group. For example, a compound of compound410.00 may be an acyl halide (e.g., L represents halo) or an acylanhydride, (e.g., L is --O--C(O)--R). The leaving group may also bealkoxy, in which case the compounds of Formula 400.00 may be produced byrefluxing a compound of Formula 405.00 with an excess of a compound ofFormula 410.00.

Compounds of Formula 405.00 may be prepared by cleaving the groupCOOR^(a) from the corresponding carbamates 415.00, for example, via acidhydrolysis (e.g., HCl) or base hydrolysis (e.g., KOH): ##STR56## whereinR^(a) is a group which does not prevent the cleavage reaction, e.g.,R^(a) is an optionally substituted alkyl such as ethyl.

Alternatively, depending upon the nature of R^(a), as determined by oneskilled in the art, Compound 415.00 may be treated with anorganometallic reagent (e.g., CH₃ Li), a inductive reagent (e.g., Zn inacid), etc., to form compounds of Formula 405.00.

Compound 415.00 may be prepared from the N-alkyl compound shown asFormula 420.00 below, in the manner disclosed in U.S. Pat. Nos.4,282,233 and 4,335,036. ##STR57##

It also will be apparent to one skilled in the art that there are othermethods for converting Compound 420.00 to Compound 405.00. For example,treatment of Compound 420.00 with BrCN via von Braun reaction conditionswould provide nitrile 420.00a. Subsequent hydrolysis of the nitrileunder either aqueous basic or acidic conditions would produce Compound405.00. This method is preferable when there is substitution on thepiperidine or piperazine ring. ##STR58##

C. The compounds of Formula 400.00 wherein Z is O or S may be made by analternative process using direct conversion of the N-alkyl compound420.00 with an appropriate compound of Formula 410.00 such as an acylhalide or acyl anhydride. Preferably the reaction is run in the presenceof an appropriate nucleophile (e.g. LiI, etc.) and solvent (e.g.,toluene, dioxane or xylenes). An appropriate base, may be added, andheating may be required. Typically, a temperature ranging from 50°-150°C. (preferably 100°-120° C.) is utilized. ##STR59## Compound 420.00 isprepared as described in part B above.

PREPARATION OF SINGLE BOND COMPOUNDS

Compounds of Formula 400.00, wherein X is carbon and the bond to carbon11 (C-11) is a single bond, can be prepared by reducing compounds ofFormula 405.00, wherein X is carbon and the bond to C-11 is a doublebond, with lithium aluminum hydride in THF. Conversion to final productscan be done following the process described above for conversion ofcompounds of Formula 405.00 to compounds of Formula 400.00.

PREPARATION OF DOUBLE BOND COMPOUNDS

Compounds of Formula 400.00, wherein X is a carbon atom having anexocyclic double bond to carbon 11, may be prepared from compound 420.00as described above. Compounds of Formula 420.00 may be produced by themethods disclosed generally in U.S. Pat. No. 3,326,924 or alternativelymay be prepared by a ring closure reaction, wherein the desiredcycloheptene ring is formed by treating compound 425.00 with a superacid. Suitable super acids for this purpose include, for example,HF/BF₃, CF₃ SO₃ H (triflic acid), CH₃ SO₃ H/BF₃, etc. The reaction canbe performed in the absence of, or with, an inert co-solvent such as CH₂Cl₂. The temperature and time of the reaction vary with the acidemployed. For example, with HF/BF₃ as the super acid system thetemperature may be controlled so as to minimize side reactions, such asHF addition to the exocyclic double bond. For this purpose, thetemperature is generally in the range of from about +5° C. to -50° C.With CF₃ SO₃ H as the super acid system, the reaction may be run atelevated temperatures, e.g., from about 25° C. to about 150° C. and atlower temperatures but the reaction then takes longer to complete.

Generally the super acid is employed in excess, preferably in amounts offrom about 1.5 to about 30 equivalents. ##STR60##

A ketone compound of Formula 425.00 may be formed by hydrolysis of430.00, e.g., such as by reacting a Grignard intermediate of Formula430.00 with an aqueous acid (e.g., aqueous HCl). I^(a) in Formula 430.00represents chloro, bromo or iodo. ##STR61##

The Grignard intermediate 430.00 is formed by the reaction of the cyanocompound 435.00 with an appropriate Grignard reagent 440.00 preparedfrom 1-alkyl-4halopiperidine. The reaction is generally performed in aninert solvent, such as ether, toluene, or THF, under general Grignardconditions e.g., temperature of from about 0° C. to about 75° C.Alternatively, other organometallic derivatives of the 1alkyl-4-halopiperidine can be employed. ##STR62##

The cyano compound of Formula 435.00 is produced by converting thetertiary butyl amide of Formula 445.00 with a suitable dehydratingagent, such as POCl₃, SOCl₂, P₂ O₅, toluene sulfonyl chloride inpyridine, oxalyl chloride in pyridine, etc. This reaction can beperformed in the absence of or with a co-solvent, such as xylene.

The dehydrating agent such as POCl₃ is employed in equivalent amounts orgreater and preferably in amounts of from about 2 to about 15equivalents. Any suitable temperature and time can be employed forperforming the reaction, but generally heat is added to accelerate thereaction. Preferably the reaction is performed at or near reflux.##STR63##

The tert-butylamide of Formula 445.00 may be produced by reaction of acompound of Formula 450.00a and 450.00b. in the presence of base,wherein G is chloro, bromo or iodo. ##STR64##

The compound of Formula 450.00a may be formed by hydrolysis of thecorresponding nitrile wherein the appropriate cyanomethyl pyridine, suchas 2-cyano-3-methylpyridine, is reacted with a tertiary butyl compoundin acid, such as concentrated sulfuric acid or concentrated sulfuricacid in glacial acetic acid. Suitable tertiary butyl compounds include,but am not limited to, t-butyl alcohol, t-butyl chloride, t-butylbromide, t-butyl iodide, isobutylene or any other compound which underhydrolytic conditions forms t-butyl carboxamides with cyano compounds.The temperature of the reaction will vary depending upon the reactants,but generally the reaction is conducted in the range of from about 50°C. to about 100° C. with t-butyl alcohol. The reaction may be performedwith inert solvents, but is usually run neat.

An alternative process for the formation of compounds of Formula 400.00amay involve direct cyclization of Compound 455.00 as shown below.##STR65##

Cyclization to form the cycloheptene ring may be accomplished with astrong acid (e.g., triflic, polyphosphoric, HF/BF₃), and may beperformed in an inert solvent, such as ether, toluene or THF. Thetemperature and time may vary with the acid employed, as described inprocess A above.

Compounds of Formula 455.00 wherein Z=O or S may be prepared by treatinga compound of Formula 425.00 with an appropriate acyl halide or acylanhydride of formula 410.00. Most preferably this reaction is run in thepresence of a good nucleophile, such as LiI, in the appropriate solvent,such as toluene, dioxane or xylene, and at a temperature ranging from50°-150° C., preferably 100°-120° C. ##STR66##

A second method of preparing compounds of Formula 455.00 involvesreacting an unsubstituted piperidylidene compound of Formula 460.00 withthe appropriate acyl halide or acyl anhydride of Formula 410.00 in thepresence of base, such as pyridine or Et₃ N. Alternatively, if L=OH incompound 410.00, then coupling of compound 460.00 with compound 410.00may require use of a conventional coupling reagent, such as DCC or CDI.##STR67##

Compounds of Formula 460.00 may be produced from the correspondingcarbamates of Formula 465.00, via acid hydrolysis, using for example,aqueous HCl, or base hydrolysis using for example, KOH. Alternatively,some compounds can be prepared by treating the carbamate, Formula465.00, with an organometallic reagent, such as methyl lithium or areductive reagent, such as zinc in acid, etc., depending upon the natureof the R^(a) group. For example, if R^(a) is a simple alkyl group, CO₂R^(a) may be cleaved by alkaline hydrolysis at 100° C. ##STR68##

The carbamate compounds of Formula 465.00 may be prepared from theappropriate alkyl compound of Formula 425.00 by treatment with achloroformate, preferably in an inert solvent, such as toluene, withwarming to approximately 80° C. Other alternative methods are availablefor the conversion of 425.00 to 455.00 as previously described (e.g. VonBraun reaction conditions). Compounds of Formula 425.00 may be preparedas described above.

SUBSTITUTION ON THE PYRIDINE RING

Various methods can be used as described in WO 88/03138 to providecompounds which are substituted on the pyridine ring, i.e., in positions2-, 3- and or 4- positions of the tricyclic ring system. For example,the cyclization methods described on pages 20-30 of WO 88/03138 canalready have the appropriate substituents on the pyridine ring in place.A variety of substituted pyridines are known in the literature and canbe employed in these syntheses. Alternatively, the azaketone of FormulaXIX (from page 27 of WO 88/03138) ##STR69## wherein R¹ and R² are both Hcan be converted to the appropriately substituted azaketone wherein R¹and R² are non-H substitutents. If both R¹ and R² are desired to benon-H substitutents the procedure would be repeated.

The azaketone is thus reacted with an oxidizing agent such asmeta-chloroperoxybenzoic acid (MCPBA) or hydrogen peroxide to producethe corresponding compound in which the nitrogen of the pyridine ring isas an N-oxide: ##STR70## wherein one of a', b', c' or d' is N→O and theothers are CH or CR¹ or CR². This reaction is normally run attemperatures from -15° C. to reflux, more typically at about 0° C. Thereaction is preferably conducted in an inert solvent such as CH₂ Cl₂ forMCPBA or acetic acid for hydrogen peroxide.

The azaketone N-oxide of Formula 470.00a can then be reacted with achlorinating agent such as SO₂ Cl₂ or SOCl₂ to form a compound ofFormula 470.00b. Typically, this reaction results in monosubstitution ofCl in the ortho or para-position relative to the N atom of the ring.##STR71##

To provide the disubstituted products, steps 1 and 2 above are repeated.##STR72## Typically, the resulting disubstituted compounds have Cl orthoand para relative to the N atom of the pyridine ring.

The mono or disubstituted compounds of Formulas 470.00b and 470.00cabove can be reacted with various nucleophiles such as alkoxides,amines, thiols, etc. This will result in compounds where one or both ofthe Cl substituents are replaced by the nucleophile to provide acompound of Formula 470.00d or a compound easily converted to Formula470.00d. ##STR73##

The substituted ketone of Formula 470.00 can then be converted to thedesired compound by the methods described above and in WO 88/03138 andin U.S. Pat. No. 3,326,924.

Formula 405.00, wherein R¹ or R² are chlorine, can be made by thefollowing alternate process. ##STR74##

The N-oxide of Formula 415.00 can be treated with POCl₃ to form acompound of Formula 415.01. Typically, this reaction results inmono-substitution of Cl in the ortho or para position relative to the Natom of the ring.

Alternatively, the Cl substituted azaketones of Formula 470.00b or470.00c above can be converted to the corresponding derivatives ofFormula 405.00 above wherein R¹ and/or R² is Cl by methods analogous tothose described above. At this point the Cl substituent(s) can bedisplaced by an appropriate nucleophile to provide the desiredsubstituent. Suitable nucleophiles include alkoxide, amines, thiols,etc. This reaction usually requires higher tempertures (e.g., from about100° to about 200° C.) than the displacement reaction to produce ketone470.00d above. It is also usually conducted in a sealed vessel in aninert solvent. The compound of Formula 405.00 is then converted to acompound of Formula 400.00 as described above.

Various electrophilic species can also be added to the pyridine ringfrom the corresponding halo-substituted pyridine (Formula 405.00 whereinR¹ is halo, preferably bromo or iodo). Transmetallation of the haloderivative using an alkyl lithium (e.g. n-BuLi) provides the lithioderivative, which can then be quenched with the appropriate electrophile(e.g. R¹ L, etc.).

An alternative process for introducing substituents at the C-3 positionof pyridine Ring I of Formula 1.0, involves nitrating a compound ofFormula 415.00 (except wherein X is nitrogen) or a compound of Formula470.00d with tetrbutylammonium nitrate--TFAA in CH₂ Cl₂ at a temperatureof 0° C. to room temperature (about 25° C.). The nitro group may then bereduced to the corresponding amine using iron filings in EtOH, orpowdered zinc--acetic acid in aqueous THF, or powdered Zn and eitherCuCl₂ or CuBr2 in aqueous EtOH. By methods know to those skilled in theart, the amine group can be converted to a variety of substituents, suchas, halo, cyano, thio, hydroxyl, alkyl, alkenyl, alkynyl and haloalkyl.

Wherein Z represents sulfur, a compound of Formula 400.00 wherein Z isoxygen is reacted with P₂ S₅, Lawesson's reagent, or another reagentcapable of introducing sulfur in place of oxygen. The reaction may takeplace at elevated temperature in pyridine, toluene or other suitablesolvents. In this and other reactions, numerous conversions of acompound of Formula 400.00 (Z=O) to another compound of Formula 400.00(Z=S) are possible.

PREPARATION OF C5-C6-ENE DERIVATIVES

Compounds of formula 400.00 with a double bond between C-5 and C-6 canbe prepared by heating a compound of Formula 470.00h in acetic acid withSeO₂ to produce a compound of Formula 470.00i. Compounds of Formula470.00i can be converted to final products according to methods alreadydescribed. ##STR75##

PREPARATION OF PIPERAZINE ANALOGS

Compounds having a piperazine ring bound to the C-11 of the tricyclicnucleus, i.e., Formula 1.0 wherein X is N, are best prepared viaalkylation of the appropriately substituted piperazine compound ofFormula 700.00 with a compound of Formula 705.00. Compounds of Formula705.00 contain the appropriately substituted halide (such as Cl, Br, orI) or other similar leaving group (e.g., tosyloxy or mesyloxy). Thereaction is usually conducted in an inert solvent, such as THF ortoluene, optionally with a base such as Et₃ N or potassium carbonate,and typically at a temperature range of ambient to reflux to produce acompound of Formula 710.00. ##STR76## In this reaction R^(g) is H, CO₂R^(a) (wherein R^(a) is a C₁ to C₄ alkyl group) or C(Z)R. Thepreparation of compound 705.00 wherein L is Cl is analogous to theprocedure described in U.S. Pat. No. 3,409,621. One skilled in the artcan prepare other derivatives of 705.00 (e.g., L is Br, I, mesyloxy, ortosyloxy). When R^(g) is H, C(Z)R or CO₂ R^(a), these are converted tocompounds of the invention by processes known in the art.

An alternate mute for generating the compound of Formula 710.00 is byreductive amination of the aza ketone 715.00 with the piperazine 700.00##STR77##

The reaction is typically carried out in a polar solvent, such as MeOHor EtOH, optionally in the presence of a dehydrating agent, such as 3 Åmolecular sieves. The intermediate Schiff base can be reduced to thecompound of Formula 710.00 by employing a variety of reducing agents,such as NaCNBH₃, or catalytic hydrogenation, for example, hydrogen overPd/C.

When R^(g) is C(Z)R, these are the compounds of the invention. WhenR^(g) is H or CO₂ R^(a), these are converted to compounds of theinvention as described herein.

Compounds of Formulas 5.3A and 5.3B, wherein R²⁵ represents a pyridylN-oxide, can be produced by reacting compounds of Formulas 5.3A and5.3B, wherein R²⁵ is pyridyl, with a one molar equivalent of anoxidizing agent (such as oxone).

Compounds of Formulas 5.3, 5.3A and 5.3B, wherein R²⁵ represents apyridyl N-oxide, can be produced by reacting the product of PreparativeExample 12 with a peroxyacid (such as MCPBA) to give the correspondingN-oxide intermediate. The desired N-oxide product may be obtained fromthe N-oxide intermediate by following the procedure of Example 183.

Compounds of the formula 7.0a, 7.0b and 7.0c can be prepared from aminesof the formula 7.1a, 7.1b and 7.1c, respectively, by coupling a compoundof the formula 7.0a, 7.0b or 7.0c with a carboxylic acid of the formulaRCOOH via the method described above for reacting compounds of theformula 405.00. ##STR78##

Alternatively, a compound of the formula 7.0a, 7.0b or 7.0c is treatedwith a compound of the formula RC(O)L, where L is a suitable leavinggroup, via the procedure described above for compounds of the formula405.00.

Compounds of the formula 7.1a can be prepared from a compound of theformula 420.50, (i.e., a compound of the formula 420.00 wherein A and Bare both H, no double bond is present between carbons 5 and 6, orbetween carbon 11 and X, X is CH, and the N-alkyl group is a methylgroup) as shown in Reaction Scheme 1. ##STR79##

In Step A of Reaction Scheme 1, a compound of the formula 420.50 isreacted with a strong base, such as an lithium diisopropylamide or analkyllithium reagent (e.g., n-butyllithium), at -100° to -10° C.,preferably at -80° to -20° C., then treated with methyl iodide to form acompound of formula 7.2a.

In Step B of Reaction Scheme 1, a compound of the formula 7.2a isconverted to a compound of the formula 7.3a via substantially the sameprocedure as described above for formation of compounds of the formula415.00.

In Step C of Reaction Scheme 1, a compound of the formula 7.3a ishydrolyzed via essentially the same procedure as described above forformation of compounds of formula 405.00, to form a compound of theformula 7.1a.

Compounds of the formula 7.1b can be prepared from a compound of the420.51 (i.e., a compound of the formula 420.00 wherein A and B are bothH, no double bond is present between carbons 5 and 6, a double bond ispresent between carbon 11 and X, X is C, and the N-alkyl group is amethyl group) via the process shown in Reaction Scheme 2. ##STR80##

In Step A of Reaction Scheme 2, a compound of the formula 420.51 isreacted with a strong base, such as an lithium diisopropylamide or analkyllithium reagent (e.g., n-butyllithium), at -100° to -10° C.,preferably at -80° to -20° C., then treated with a protic solvent, suchas an alcohol, preferably MeOH, to form a compound of formula 7.2b.

In Step B of Reaction Scheme 2, a compound of the formula 7.2b isconvened to a compound of the formula 7.3b via substantially the sameprocedure as described above for formation of compounds of the formula415.00.

In Step C of Reaction Scheme 2, a compound of the formula 7.3b ishydrolyzed via essentially the same procedure as described above forformation of compounds of formula 405.00, to form a compound of theformula 7.1b.

Compounds of the formula 7.1c can be prepared from a compound of the420.51 via the process shown in Reaction Scheme 3. ##STR81##

In Step A of Reaction Scheme 3, a compound of the formula 420.51 isreacted with a strong base, such as an lithium diisopropylamide or analkyllithium reagent (e.g., n-butyllithium), at -100° to -10° C.,preferably at -80° to -20° C., then treated with methyl iodide to form acompound of formula 7.2c.

In Step B of Reaction Scheme 3, a compound of the formula 7.2c isconverted to a compound of the formula 7.3c via substantially the sameprocedure as described above for formation of compounds of the formula415.00.

In Step C of Reaction Scheme 1, a compound of the formula 7.3c ishydrolyzed via essentially the same procedure as described above forformation of compounds of formula 405.00, to form a compound of theformula 7.1c.

In the above processes, it is sometimes desirable and/or necessary toprotect certain R¹, R², R³ and R⁴ etc., groups during the reactions.Conventional protecting groups are operable as described in Greene, T.W., "Protective Groups In Organic Synthesis," John Wiley & Sons, NewYork, 1981. For example, the groups listed in column 1 of Table 1 may beprotected as indicated in column 2 of the table:

                  TABLE 1                                                         ______________________________________                                        PROTECTED GROUPS                                                              1. GROUP TO BE                                                                PROTECTED     2. PROTECTED GROUP                                              ______________________________________                                        COOH                                                                                         ##STR82##                                                       ##STR83##                                                                                   ##STR84##                                                       ##STR85##                                                                                   ##STR86##                                                      OH                                                                                           ##STR87##                                                      NHR, wherein R is any substituent on an amino group within the scope of       the claims                                                                                   ##STR88##                                                      NH.sub.2                                                                                     ##STR89##                                                      ______________________________________                                    

Other protecting groups well known in the art also may be used. Afterthe reaction or reactions, the protecting groups may be removed bystandard procedures.

Compounds useful in this invention are exemplified by the followingpreparative examples, which should not be construed to limit the scopeof the disclosure. Alternative mechanistic pathways and analogousstructures within the scope of the invention may be apparent to thoseskilled in the art.

PREPARATIVE EXAMPLE 1 A. N-(1,1-DIMETHYLETHYL)-3-METHYL-2-PYRIDINECARBOXAMIDE ##STR90##

Suspend 2-cyano-3-methyl pyridine (400 g) in t-butanol (800 mL) and heatto 70° C. Add concentrated sulphuric acid (400 mL) dropwise over 45minutes. Maintain the temperature at 75° C., until the reaction iscomplete, and for an additional 30 minutes. Dilute the mixture withwater (400 mL), charge with toluene (600 mL) and bring to pH 10 withconcentrated aqueous ammonia. Maintain the temperature at 50°-55° C.during the work up. Separate the toluene phase, and reextract theaqueous layer. Combine toluene phases and wash with water. Remove thetoluene to yield the title compoundN-(1,1-dimethylethyl)-3-methyl-2-pyridine carboxamide, as an oil, fromwhich solid product is crystallized. (Yield 97%, as determined by aninternal standard assay with gas chromatography).

B. 3- 2-(3-CHLOROPHENYL)ETHYL!-N-(1,1-DIMETHYLETHYL)-2-PYRIDINECARBOXAMIDE ##STR91##

Dissolve the title compound of Preparative Example 1A,N-(1,1-dimethylethyl)-3-methyl-2-pyridine carboxamide (31.5 g.) in THF(600 mL) and cool the resulting solution to -40° C. Add n-butyllithium(2 eq.) in hexane while maintaining the temperature at -40° C. Thesolution turns deep purple-red. Add sodium bromide (1.6 g) and stir themixture. Add solution of m-chlorobenzylchloride (26.5 g., 0.174 mole) inTHF (125 mL) while maintaining the temperature at -40° C. Stir thereaction mixture until the reaction is complete as determined by thinlayer chromatography. Add water to the reaction until the color isdissipated. Extract the reaction mixture with EtOAc, wash with water,and concentrate to a residue which is the title compound. (Yield 92% asshown by chromatography).

C. 3- 2-(3-CHLOROPHENYL)ETHYL!-2-PYRIDINE-CARBONITRILE ##STR92##

Heat a solution of the title compound of Preparative Example 1B, 3-2-(3-chlorophenyl)ethyl!-N-(1,1-dimethylethyl)-2-pyridine carboxamide(175 g, 0.554 mole) in phosphorous oxychloride (525 mL, 863 g, 5.63mole) and reflux for 3 hours. Determine completion of the reaction bythin layer chromatography. Remove any excess phosphorous oxychloride bydistillation at reduced pressure and quench the reaction in a mixture ofwater and isopropanol. Bring to pH 5-7 by adding 50% aqueous NaOHsolution while maintaining the temperature below 30° C. Filter thecrystalline slurry of crude product and wash with water. Purify thecrude product by slurrying the wet cake in hot isopropanol, and cool to0°-5° C. Filter the product, wash with hexane and dry at a temperaturebelow 50° C. to yield the title compound. (Yield: 118 g (HPLC purity95.7%), m.p. 72° C.-73° C., 89.4% of theory).

D. 1-(METHYL-4-PIPERIDINYL)3-(2-(3-CHLOROPHENYL)ETHYL)-2-PYRIDINYL!METHANONE HYDROCHLORIDE##STR93##

Dissolve the title compound of Preparative Example 1C, (118 g, 0.487mole) in dry THF (1.2 L) and add N-methyl-piperidyl magnesium chloride(395 mL, 2.48 mole/liter, 0.585 mole, 1.2 eq.) over 15 minutes. Maintainthe temperature at 40° C.-50° C. by cooling with water as necessary, for30 minutes. Determine completion of the reaction by thin layerchromatography. Quench the reaction by reducing the pH to below 2 with2N HCl and stir the resulting solution at 25° C. for 1 hour. Remove thebulk of the THF by distillation and adjust the resulting solution to pH3.5 by addition of aqueous NaOH. Cool to 0° to 5° C. and filter off thecrystalline hydrochloride salt product. Wash with ice cold water and dryto constant weight at 60° C. to yield the title compound. (Yield: 168.2g (HPLC purity 94%), m.p. 183°-185° C., 89% of theory).

E. 8-CHLORO-11-(1-METHYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO5,6!CYCLOHEPTA 1,2-b!PYRIDINE ##STR94##

Dissolve the title compound of Preparative Example 1D above (59 g, 0.15mole) in hydrofluoric acid (120 mL, 120 g, 6.0 mole) at -35° C. and addboron trifluoride (44.3 g, 0.66 mole) over 1 hour. Determinecompleteness of the reaction by thin layer chromatography. Quench thereaction using ice, water and KOH bringing the solution to a final pH of10. Extract the product with toluene and wash with water and brine.Concentrate the toluene solution to a residue, and dissolve in hothexane. Remove the insolubles by filtration and concentrate the filtrateto yield the title compound as an off-white powder. (Yield: 45.7 g (HPLCpurity: 95%), 92% of theory).

Alternative Step E:

8-CHLORO-11-(1-METHYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO5.6!CYCLOHEPTA 1,2-b!PYRIDINE

React the title compound of Preparative Example 1D above (177 g, 0.49mole) in trifluoromethanesulfonic acid (480 ml, 814.1 g, 5.31 mole) at90°-95° C. for 18 hours under nitrogen. Determine the completeness ofthe reaction by thin layer chromatography. Cool the reaction and quenchthe reaction with ice-water and adjust the pH to 6 with bariumcarbonate. Extract the product with CH₂ Cl₂, and concentrate underreduced pressure to about 1 liter. Wash with water, and extract theproduct into 1N HCl which is treated with 30 g of activated charcoal,and filter through celite. Adjust the pH of the filtrate to 10 withaqueous NaOH (50%), extract the product into CH₂ Cl₂, and remove underreduced pressure to form a residue. Dissolve the residue in hot hexane,and filter to remove insolubles. Concentrate the filtrate to yield thetitle compound as a beige powder. (Yield: 126 g (HPLC purity 80%), 65%of theory).

F. 8-CHLORO-11-(1-ETHOXYCARBONYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO5,6!CYCLOHEPTA 1,2-b!PYRIDINE ##STR95##

Dissolve the title compound of Preparative Example 1E above (45.6 g,0.141 mole) in toluene (320 mL) at 80° C. and to it gradually add ethylchloroformate (40.4 mL, 45.9 g, 0.423 mole). Following completeaddition, maintain the temperature at 80° C. for 1 hour, then adddiisopropylethylamine (2.7 mL, 2.00 g, 0.016 mole) and additional ethylchloroformate (4.1 mL, 4.65 g, 0.0429 mole). Monitor completeness of thereaction by thin layer chromatography. Upon completion, cool thereaction mixture to ambient temperature, and wash the toluene solutionwith water. Concentrate the organic layer to a residue and dissolve inhot acetonitrile (320 mL). Decolorize the solution with 14 g ofactivated charcoal. Remove the activated charcoal by filtration andconcentrate the filtrate to a crystalline slurry. Cool the mixture to0°-5° C., and isolate the product by filtration. Wash with coldacetonitrile and dry the product at below 70° C. to yield the titlecompound. (Yield: 42.4 g (HPLC purity 97.4%), 80% of theory).

G. 8-CHLORO-11-(4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO 5,6 CYCLOHEPTA1,2-b!PYRIDINE ##STR96##

Hydrolize the title compound of Preparative Example 1F,8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo5,6!cyclohepta 1,2-b!pyridine (39 g, 0.101 mole) with KOH (50 g) in EtOH(305 mL) and water (270 mL) at reflux under an argon atmosphere for 64hours. Partially distill off the EtOH and dilute the residue with brine,and extract with EtOAc (3×). Wash the combined organic phases with waterand dry with Na₂ SO₄. Remove the solvent to give a solid which can berecrystallized from toluene to give the title compound as a white solid.(Yield: 24.5 g, 77%, melting point 154°-155° C.).

H. By substituting in step 1B above, the benzylic halide: ##STR97## formeta-chlorobenzylchloride, and employing basically the same methods assteps C through G, the compound ##STR98## is prepared. Dichloro compound(I) is recrystallized from toluene and has a melting point of 150°-152°C. Reaction times are determined by TLC or HPLC. In some instancespurification of the product by chromatography is necessary.

PREPARATIVE EXAMPLE 2 A.N-(1,1-DIMETHYLETHYL)-3-2-(4-FLUOROPHENYL)ETHYL!-2-PYRIDINE CARBOXAMIDE##STR99##

Cool a solution of N-(1,1-dimethylethyl)-3-methyl-2-pyridine-carboxamide(38.4 g, 0.2 mole) in dry THF (250 mL) to -40° C. and add n-butyllithium (185 mL, 0.44 mole). Add sodium bromide (1.9 g, 18 mmol.) andstir for 15 minutes. Add 4-fluorobenzylchloride (31.8 g, 0.22 mole) andstir for 2.5 hours while warming to -5° C. Quench the reaction withwater and extract the product twice with EtOAc, then wash with brine(2×). Dry the organic phase over Na₂ SO₄, filter and remove the solventto give the title compound. (60.0 g, Yield 99%, m.p. 59°-61° C.)

B. 3- 2-(4-FLUOROPHENYL)ETHYL!-2-PYRIDINE CARBONITRILE ##STR100##

Heat the title compound of Preparative Example 2A above (60.0 g, 0.2mole) in POCl₃ (200 mL) to 110° C. under an argon atmosphere for 3.5hours. Pour the reaction mixture onto ice and basify with NaOH (50%)solution. Extract the mixture with EtOAc (3×) and wash with water. Washwith brine and dry over Na₂ SO₄. Remove the solvent and pass the residuethrough a coarse SiO₂ (60-200 mesh) column to give the title compound asa white solid (40 g, Yield 88%, m.p. 48°-49° C.).

C. 9-FLUORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA 1,2-b!PYRIDIN-11-ONE##STR101##

Cyclize the title compound of Preparative Example 2B above (31.5 g, 139mmol) in polyphosphoric acid (1.24 kg) at 200° C. for 5.5 hours. Pouronto ice and basify with NaOH solution (50%). Extract the product withchloroform (3×) and wash with brine. Dry the organic phase with Na₂ SO₄,filter and remove the solvent to give the title compound (20.4 g, yield64%, m.p. 78°-81° C. after recrystallization from diisopropyl ether).

D. 9-FLUORO-11-(1-METHYL-4-PIPERIDINYL)-6,11-DIHYDRO-5H-BENZO5,6!CYCLOPHEPTA 1,2-b!PYRIDIN-11-OL ##STR102##

Dissolve the title compound of Preparative Example 2C above (10.0 g, 44mmol) in THF (100 mL) and add slowly to a cooled (-40° C.) solution ofthe Grignard reagent prepared from N-methyl-4-chloropiperidine (57.9 mL,88 mmol) and magnesium in THF (70 mL). Stir the mixture for about 1 hourwhile warming up to 0° C. Quench the reaction with NH₄ Cl solution andextract with EtOAc (2×). Wash the organic phase with brine and dry overNa₂ SO₄, filter and remove the solvent. Purify the residue with flashchromatography and elute with MeOH (5%) in CHCl₃ to give the titlecompound as white granular crystals. (10.1 g, Yield 70%, m.p. 126°-127°C. after recrystallization from diisopropyl ether.)

E. 9-FLUORO-11-(1-METHYL-4-PIPERIDYLENE)-6,11-DIHYDRO-5H-BENZO5,6!CYCLOHEPTA 1,2-b!PYRIDINE ##STR103##

Add the title compound of Preparative Example 2D above (7.3 g, 22.3mmol) to a mixture of cooled H₂ SO₄ and CF₃ SO₃ H (1:1), (146 mL). Stirthe reaction mixture for 0.5 hours at ice bath temperature and then atroom temperature for 1.5 hours. Pour the reaction mixture onto ice andbasify with NaOH (50%) solution. Extract the product with EtOAc (3×) andwash with brine. Dry the organic phase over Na₂ SO₄, filter and removethe solvent to give a crude oil. Charcoal the oil and recrystallize fromEtOAc and isopropyl ether to give the title compound. (5.6 g, Yield 82%,m.p. 134.5°-135.5° C.).

F. 9-FLUORO-11-(1-ETHOXYCARBONYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO5,6!CYCLOHEPTA 1,2-b!PYRIDINE ##STR104##

Stir a solution of the title compound of Preparative Example 2E above(5.0 g, 16.2 mmol) and Et₃ N (2.6 g, 26 mmol) in dry toluene (60 mL) at80° C. under an argon atmosphere, and add ethyl chloroformate (9.8 g, 90mmol) via a syringe. Stir the reaction at this temperature for 30minutes and at room temperature for one hour. Filter the reaction andremove the solvent. Pass the residue through a coarse SiO₂ column(60-200 mesh), and elute with CHCl₃ to yield the title compound as awhite solid. (4.5 g, Yield 76%, m.p. 112°-114° C. after trituration withpentane).

G. 9-FLUORO-11-(4-PIPERIDYLIDENE-6,11-DIHYDRO-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDINE ##STR105##

Reflux the title compound of Preparative Example 2F above (3.83 g, 10.4mmol) with KOH (4.6 g) in 50 mL of EtOH/H₂ O (1:1) for 4 hours under anargon atmosphere. Pour the reaction mixture into a brine solution andextract with EtOAc (2×), dry over Na₂ SO₄ and filter. Remove the solventto give the title compound (2.86 g, Yield 90%, m.p. 138°-140° C.).

H. By employing the benzyl halide ##STR106## in place of 4-fluorobenzylchloride in step 2A above, the product ##STR107## is prepared (m.p.138°-140° C., triturated with pentane) by employing basically the sameprocess as described in steps 2A-2G. Workup time is determined by eitherTLC or HPLC. In some instances purification of the product bychromatography is necessary.

PREPARATIVE EXAMPLE 3 A. 3.5-DIMETHYLPYRIDINIUM N-OXIDE ##STR108##

A solution of 285 mL (1.31 mol) of 35% peracetic acid was slowly addedto a stirred solution of 149 g (1.39 mol) of 3,5-dimethylpyridine duringwhich the temperature rose to 85° C. and was maintained at thistemperature during addition. After the temperature of the mixturedropped to about 35° C. the reaction was stored at 5° C. overnight.

After partial removal of 185 ml of acetic acid via distillation undervacuum, the reaction was washed with NaHSO₄ solution and thenneutralized with 10% NaOH solution to pH of about 7. The product wasextracted with CH₂ Cl₂ to give the title compound as a white solid(yield 142 g, 83%).

B. 1-METHOXY-3,5-DIMETHYLPYRIDINIUM METHYL SULFATE ##STR109##

Dimethylsulfate (42.0 g, 0.33 mol) was slowly added to 41.0 g (0.33 mol)of 3,5-dimethylpyridinium N-oxide with mechanical stirring. The mixturewas then heated on a steam bath for 1 hr. Then vacuum was applied whilecooling to give a brownish solid of the title compound in quantitativeyield.

C. 2-CYANO-3,5-DIMETHYLPYRIDINE ##STR110##

To a cooled (0° C.) solution of sodium cyanide (49.0 g, 0.999 mol, 3.0eq.) in 135 mL of water (air free) was dripped 1-methoxy-3,5-dimethylpyridinium methyl sulfate (83.0g, 0.33 mol) in 100 mL water (air free)in 1.25 hr., keeping the temperature below 3° C. The reaction mixturewas stored at about 3° C. overnight. The mixture was filtered and washedwith water to give 40 g of the title compound. An analytical sample wasrecrystallized from isopropyl ether and pentane (4:1) (m.p.: 61°-62°C.).

D. N-(1,1-DIMETHYLETHYL)-3,5-DIMETHYL-2-PYRIDINE CARBOXAMIDE ##STR111##

To a stirred solution of 20.3 g (0.153 mol) of2-cyano-3,5-dimethylpyridine in 100 mL of 20 mL of conc. sulfuric acidwithin 10 minutes, followed by 20 mL of t-butanol over an additional 15minutes. The solution was warmed at 75° C. for 30 minutes after which itwas cooled to room temperature and basified with 25% NaOH. The productwas extracted 3× with EtOAc (600 mL), which was combined and washed 1×with brine, dried (Na₂ SO₄), filtered and concentrated in vacuo to givethe title compound (31.26 g) as a yellowish oil.

E. 8-CHLORO-3-METHYL-11-(4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO5,6!CYCLOHEPTA 1,2-b!PYRIDINE ##STR112##

By substituting in step 1B aboveN-(1,1-dimethylethyl)-3,5-dimethyl-2-pyridine carboxamide forN-(1,1-dimethylethyl)-3-methyl-2-pyridine carboxamide and employingbasically the same methods as steps B through G of Preparative Example1, one obtains8-chloro-3-methyl-11-(4-piperidylidene)-6,11-dihydro-5H-benzo5,6!cyclohepta 1,2-b!pyridine. Reaction times are determined by TLC orHPLC.

PREPARATIVE EXAMPLE 4

By substituting ##STR113## for 3,5-dimethylpyridine in PreparativeExample 3 above and following basically the same procedure (steps A-E),the compounds ##STR114## respectively, can be prepared. Note that theaddition of the nitrile group to the pyridine in Step C of PreparativeExample 3 can result in the formation of other undesirable isomers whichcan be removed via flash chromatography.

PREPARATIVE EXAMPLE 5 A. 8-CHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-ONE N-OXIDE ##STR115##

To a mixture of 25.1 grams (0.103 mole) of8-chloro-5,6-dihydro-11H-benzo 5,6!cyclohepta 1,2-b!pyridin-11-one in175 ml of dry CH₂ Cl₂ at 0° C. under an argon atmosphere was addeddropwise over 70 minutes a solution of 24.12 grams of3-chloroperoxy-benzoic acid in 150 ml of CH₂ Cl₂. After the addition thesolution was stirred for 1/2 hour after which the ice bath was removed.After two days the reaction was poured into 1.0N aqueous NaOH andextracted with CH₂ Cl₂. The organic portions were combined, washed oncewith water, dried over MgSO₄, filtered and concentrated in vacuo. Theresultant product was triturated with isopropyl ether and filtered toprovide 25.8 grams (96%) yield of the title compound.

B. 2,8-DICHLORO-5,6-DIHYDRO-11H-BENZO 5,6!-CYCLOHEPTA1,2-b!PYRIDIN-11-ONE AND 4,8-DICHLORO-5,6-DIHYDRO-11H-BENZO5,6!CYCLOHEPTA 1,2-b!PYRIDIN-11-ONE ##STR116##

To a mixture of 29.13 grams (112.2 mmol) of the title compound fromPreparative Example 5A above, in 40 ml of dry CH₂ Cl₂ at 0° C. and underargon atmosphere was added 500 ml of 1.0M SO₂ Cl₂ dropwise over 1 hour.The ice bath was then removed and the reaction stirred at roomtemperature for 1 hr and then refluxed for seven hours. The mixture waspoured into 1.0N aqueous NaOH and extracted three times with CH₂ Cl₂.The organic portions were combined, dried over MgSO₄, filtered andconcentrated in vacuo to yield a product which was purified andseparated via flash chromatography to yield the two title compounds.

C. 4-(2,8-DICHLORO-5,6-DIHYDRO-11H-BENZO 5,6!-CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE)PIPERIDINE AND4-(4,8-DICHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA-1,2-b!PYRIDIN-11-YLIDENE)PIPERIDINE ##STR117##

By following essentially the same procedure as that described in partsD-G of Preparative Example 2 above, the 2,8-dichloro and 4,8-dichloroproducts of Preparative Example 5B above were converted to thecorresponding title compounds.

PREPARATIVE EXAMPLE 6 A.3-(1,1-DIMETHYL-1-ETHYL)-8-CHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-ONE ##STR118##

To a mixture of 20.05 grams (82.28 mmol) of8-chloro-5,6-dihydro-11H-benzo 5,6!cyclohepta 1,2-b!pyridin-11-one in400 ml of dry THF at -72° C. and under an atmosphere of nitrogen wasadded dropwise over 40 minutes 66.0 ml of 2.7M t-butyl magnesiumchloride in THF. The reaction mixture was slowly warmed to roomtemperature and stirred overnight. The mixture was then poured into 10%aqueous ammonium chloride and extracted four times with CH₂ Cl₂. Thecombined organic portions were dried over MgSO₄, filtered, andconcentrated in vacuo to give the title tom pound, along with8-chloro-11-(1,1-dimethyl-1-ethyl)-6,11-dihydro-5H-benzo 5,6!cyclohepta1,2-b!pyridin-11-ol. These compounds were separated via flashchromatography to give the title compound, which was recrystallized fromisopropyl ether to give 4.37 grams (18%) of the title compound as awhite solid.

B. 4- 3-(1,1-DIMETHYL-1-ETHYL)-8-CHLORO-5,6-DIHYDRO-11H-BENZO5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!PIPERIDINE ##STR119##

By using the title compound of Part A above and applying essentially thesame procedure described in parts D-G of Preparative Example 2 above,one can obtain the title compound.

PREPARATIVE EXAMPLE 7 A. 8-CHLORO-6,11-DIHYDRO-11-HYDROXY-5H-BENZO5,6!-CYCLOHEPTA 1,2-b!PYRIDINE ##STR120##

To a mixture of 25.03 g (103 mmol) of 8-chloro-5,6-dihydro-11H-benzo5,6!cyclohepta 1,2-b!pyridin-11-one in 200 mL of MeOH at roomtemperature and under a nitrogen atmosphere was added portionwise over aperiod of about 1 hour 4.82 g (124 mmol) of sodium borohydride.Occasional cooling with an ice bath was necessary at times during theaddition in order to avoid excessive reflux. After 1.6 hours the mixturewas poured into ice cold water and then extracted with EtOAc (3×). Thecombined organic portions were washed with brine, dried over MgSO₄,filtered, and concentrated in vacuo. The residue was recrystallized fromhot isopropyl ether. The remaining filtrate was purified via flashchromatography (20% EtOAc in hexanes) to yield more product whichsolidified on standing. Both batches were combined to yield 20.41 g ofthe title compound as a white solid.

B. 8,11-DICHLORO-6,11-DIHYDRO-5H-BENZO 5,6!CYCLOHEPTA 1,2-b!PYRIDINE##STR121##

To a mixture of 13.3 g (54 mmol) of8-chloro-6,11-dihydro-11-hydroxy-5H-benzo 5,6!cyclohepta 1,2-b!pyridinein 290 mL of toluene at -15° C. and under an atmosphere of nitrogen wasadded via syringe pump over a period of 1 hour 6.20 mL (85.7 mmol) ofthionyl chloride. The extent of reaction was monitored by TLC (50% EtOAcin hexanes). When completed the mixture was poured into 300 mL of 1.0Naqueous NaOH and extracted with EtOAc (5×). The combined organicportions were washed with brine, dried over sodium sulfate, filtered,and concentrated in vacuo. The residue was taken up in EtOAc, quicklyfiltered through basic alumina, and concentrated again to yield aproduct which was triturated with pentane to yield 10.22 g of the titlecompound as a tan solid.

C. 8-CHLORO-11-(1PIPERAZINYL)-6,11-DIHYDRO-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDINE ##STR122##

To a mixture of 10.0 g (37.9 mmol) of8,11-dichloro-6,11-dihydro-5H-benzo 5,6!cyclohepta 1,2-b!pyridine and1.0 ml of Et₃ N in 200 mL of dry THF at room temperature and under anitrogen atmosphere was added 33.0 g of piperazine. The mixture wasstirred at room temperature for 22.5 hours and then refluxed for 5.5hours. It was then cooled to room temperature, poured into 250 mL of 5%aqueous NaOH, and extracted with CH₂ Cl₂ (3×). The combined organicportions were washed with brine, dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified via flash chromatography(2→5% MeOH saturated with ammonia in CH₂ Cl₂) to yield the titlecompound as a glass.

PREPARATIVE EXAMPLE 8 A. ETHYL 3-PYRIDYLACETIC ACID 1-N-OXIDE ##STR123##

Ethyl 3-pyridylacetic acid (10 grams) (60.6 mmoles) was dissolved in dryCH₂ Cl₂ (120 ml) and the solution was stirred at -18° C. for 30 minutes.MCPBA (31.34 grams) (181.6 mmoles) was added and the mixture was stirredat -18° C. for 1 hour and then at 25° C. for 87 hours. The reactionmixture was diluted with CH₂ Cl₂ and washed with saturated aqueoussodium bicarbonate and then water. The CH₂ Cl₂ was then dried (magnesiumsulphate), filtered and evaporated to dryness. The residue waschromatographed on silica gel using 3% (10% concentrated ammoniumhydroxide in MeOH)--CH₂ Cl₂ as the eluant to give the title compound(Yield: 8.45 grams, 77%, MH⁺ 182).

B. 3-PYRIDYLACETIC ACID 1-N-OXIDE ##STR124##

3-Pyridylacetic acid (0.2747 grams) (1.5 mmoles) was dissolved in EtOH(200 proof) (1.22 ml.) and a 1M solution of LiOH in water (3.64 ml.)(3.0 mmoles) was added and the mixture was stirred at 25° C. for 4hours. 1N HCl (4.28 ml.) was added and the mixture was pumped down todryness on a rotary evaporator to give the title compound (Yield: 0.2931grams, 100%).

PREPARATIVE EXAMPLE 9 A. ETHYL α-METHYL-3-PYRIDYLACETIC ACID ##STR125##

To ethyl 3-pyridylacetic acid (10.86 grams) (65.7 mmoles) was added a2.0M solution of lithium diisopropylamide in THF/heptane/ethyl benzene(32.87 ml.) (65.8 mmoles) at -30° C. The semi-solid mixture was agitatedand sonicated for 1 hour. The mixture was allowed to remain at 25° C.for 1 hour, whereupon methyl iodide (4.09 ml.) (65.7 mmoles) was added.After 1 hour at 25° C. the mixture was taken up in CH₂ Cl₂ and washedwith saturated aqueous sodium bicarbonate and water. The CH₂ Cl₂ wasdried (magnesium sulphate), filtered and evaporated to dryness. Theresidue was chromatographed on silica gel using 10% EtOAc in hexane asthe eluant to give the title compound (Yield: 3.48 grams, 30%, MH⁺ 180).

B. α-METHYL-3-PYRIDYLACETIC ACID ##STR126##

The title compound from Preparative Example 9A above (2.16 grams) (12.05mmoles) was dissolved in EtOH (10 ml.) and 1.0M LiOH in water (29.15ml.) (29.2 mmoles) was added. The mixture was stirred at 25° C. for 4hours, whereupon 1N HCl (34.27 ml.) (34.2 mmoles) was added and thesolution was evaporated to dryness to give the title compound (Yield2.33 grams, 100%).

PREPARATIVE EXAMPLE 10 α,α-DIMETHYL-3-PYRIDYLACETIC ACID ##STR127##

Ethyl α,α-dimethyl -3-pyridylacetate (disclosed in EP Application 0 288279, published Oct. 26, 1988) (2.67 grams, 13.8 mmoles) was dissolved inEtOH (11.1 ml.) and a 1.0M LiOH in water (33.3 ml.) (33.4 mmoles) wasadded. The mixture was stirred at 25° C. for 4 hours. 1N HCl (38.73 ml.)was added and after 5 minutes the mixture was evaporated to dryness togive the title compound (Yield: 100%).

PREPARATIVE EXAMPLE 11 A.8-CHLORO-6,11-DIHYDRO-11-(1-PIPERAZINYL)-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDINE 1-N-OXIDE ##STR128##

To a mixture of 8-chloro-5,6-dihydro-11H-benzo 5,6!cyclohepta1,2-b!pyridin-11-one (5 grams) (20.6 mmoles) in dry CH₂ Cl₂ (35 ml) wasadded dropwise MCPBA (4.7 grams) (27.3 mmoles) in dry CH₂ Cl₂ (75 ml) at0°-25° C. over 1 hour. The mixture was diluted with CH₂ Cl₂ and washedwith saturated aqueous sodium bicarbonate and water. The CH₂ Cl₂ wasdried (magnesium sulphate), filtered and evaporated to dryness. Theresidue was chromatographed on silica gel using 1% (10% saturatedammonium hydroxide in MeOH)--CH₂ Cl₂ as the eluant to give the titlecompound (Yield: 2.81 grams, 53%, MH⁺ 260).

B. 8-CHLORO-6,11-DIHYDRO-5H-BENZO 5,6!CYCLOHEPTA 1,2-b!PYRIDIN-11-OL1-N-OXIDE ##STR129##

By using the title compound (8.6 grams) from Preparative Example 11A andreducing it by the procedure described in Preparative Example 7A abovethe title alcohol was obtained (Yield: 7.03 grams, 81%, MH⁺ 262).

C. 8,11-DICHLORO-6,11-DIHYDRO-5H-BENZO 5,6!CYCLOHEPTA 1,2-b!PYRIDINE1-N-OXIDE ##STR130##

The title compound from Preparative Example 11B (6.2 grams) (23.7mmoles) was reacted with thionyl chloride as described in PreparativeExample 7B to give the title compound.

D. 8-CHLORO-6,11-DIHYDRO-11-(1-PIPERAZINYL)-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDINE 1-N-OXIDE ##STR131##

The title compound from Preparative Example 11C above was reacted withpiperazine (9.9 grams) (115.0 mmoles) as described in PreparativeExample 7C to give the title compound (Yield: 6.78 grams, 87%, MH⁺ 330).

PREPARATIVE EXAMPLE 12 4-ETHOXYCARBONYLAMINOPYRIDINE ##STR132##

4-Aminopyridine (17.34 grams) (184.3) was dissolved in dry pyridine (217ml.) and cooled to 0° C. over 30 minutes. Ethyl chloroformate (17.2 ml.)(180.7 mmoles) was added and the solution was stirred at 0° C. for 1hour and then at 25° C. for 40 hours. The mixture was diluted with CH₂Cl₂ and washed with saturated aqueous NaHCO₃ and water. The CH₂ Cl₂ wasdried (MgSO₄), filtered and evaporated to dryness. The residue waschromatographed on silica gel using 2% (10% saturated NH₄ OH inMeOH)--CH₂ Cl₂ to give the title compound (Yield: 10 grams, 33% M⁺ 166).

By using essentially the same procedure, with the exception that##STR133## was used instead of 4-aminopyridine, the compound ##STR134##was obtained, respectively.

PREPARATIVE EXAMPLE 13 A. N-ACETYLISONIPECOTIC ACID ##STR135##

Isonipecotic acid (10 grams) (77.5 mmoles) and acetic anhydride (23.7grams) (232.5 mmoles) were dissolved in MeOH (100 ml.) and the mixturewas stirred at 25° C. for 24 hours. The mixture was evaporated todryness and the residue was azeotroped with toluene to give the titlecompound (Yield: 12.8 grams, 97%, MH⁺ 172).

B. 1-N-tert-BUTOXYCARBONYLISONIPECOTIC ACID ##STR136##

Isonipecotic acid (20 grams) (155.0 mmoles) was dissolved in THF-water(1:1) (400 ml) and NaOH (6.2 grams) (155.0 mmoles) anddi-tert-butyldicarbonate (37.2 grams) (170.5 mmoles) were added. Themixture was stirred at 25° C. for 72 hours. The solution was then elutedthrough a bed of washed BioRad 50WX4 (RSO3H resin) (150 ml bed) and theresin was eluted with a 1:1 mixture of THF and water. The eluate wasevaporated to dryness to give the title compound (yield: 33.78 grams,90%).

PREPARATIVE EXAMPLE 14 1-N-ACETYLNIPECOTIC ACID ##STR137##

Nipecotic acid (3.87 grams) (30.0 mmoles) was reacted with aceticanhydride (9.17 grams) (90 mmoles) as described in Preparative Example13A to give the title compound (Yield: 5.0 grams, 97%, MH⁺ 172).

PREPARATIVE EXAMPLE 15 1-N-METHYLNIPECOTIC ACID ##STR138##

Arecaidine hydrochloride (4 grams) (22.6 mmoles) was hydrogenated inwater (100 ml) using 10% Pd--C at 40 psi at 25° C. for 24 hours. Thecatalyst was filtered off and washed with water. The aqueous solutionwas shaken with BioRad AG1X8 resin (OH⁻ form) (23 ml bed) and after 5minutes the resin was filtered off and washed with water. The aqueoussolution was evaporated to give the title compound (Yield: 2.95 grams,92%).

PREPARATIVE EXAMPLE 16 1-N-ACETYL D,L-PIPECOLINIC ACID ##STR139##

D,L-Pipecolinic acid (10 grams) (77.5 mmoles) and acetic anhydride (23.7grams) (232.5 mmoles) were reacted as described in Preparative Example13A above to give the title compound (Yield: 12.94 grams, 98%, MH⁺ 172).

PREPARATIVE EXAMPLE 17 A. PIPERIDINE-4-ACETIC ACID ##STR140##

4-Pyridylacetic acid (7 grams) (40.4 mmoles) was hydrogenated asdescribed in Preparative Example 15 to give the title compound (Yield:5.2 grams, 90%, MH⁺ 144).

B. 1-N-ACETYL-4-PIPERIDINYLACETIC ACID ##STR141##

4-Piperidinylacetic acid (5 grams) (35.0 mmoles) was reacted with aceticanhydride (10.7 grams) (105.0 mmoles) as described in PreparativeExample 13A to give the title compound (Yield: 6.4 grams, 99%, MH⁺ 185).

C. 1-N-METHYL-4-PIPERIDINYLACETIC ACID ##STR142##

4-Piperidinylacetic acid (4 grams) (28.0 mmoles) from PreparativeExample 17A was dissolved in water (50 ml) and 37% formalin (2.72 ml)(33.6 mmoles) was added. The mixture was hydrogenated over 10% Pd--C at55 psi at 25° C. for 68 hours. The catalyst was filtered off and washedwith water. The combined filtrates were evaporated to dryness to givethe title compound (MH⁺ 158).

D. 1-N-tert-BUTOXYCARBONYLPIPERIDINYL-4-ACETIC ACID ##STR143##

4-Piperidinylacetic acid (41.24 grams) (288.4 mmoles) from PreparativeExample 17A was reacted with di-tert-butyldicarbonate (69.14 grams)(317.3 mmoles) and NaOH (11.52 grams) (288.4 mmoles) as described inPreparative Example 13B above to give the title compound (Yield: 53.0grams, 76%).

PREPARATIVE EXAMPLE 18 A. 3-PIPERIDINYLACETIC ACID ##STR144##

3-Pyridylacetic acid hydrochloride (13 grams) (74.9 mmoles) washydrogenated as described in Preparative Example 15 to give a mixture ofunreacted 3-pyridylacetic acid and the title compound (76:24) (8.63grams, MH⁺ 144).

B. 1-N-ACETYL-3-PIPERIDINYLACETIC ACID ##STR145##

The mixture of compounds from Preparative Example 18A (8.56 grams) werereacted with acetic anhydride (8.56 grams) as described in PreparativeExample 13A and the crude mixture of products was taken up in MeOH (60ml) and passed over a bed of BioRad AG50WX4 resin (RSO₃ H) and thelatter was eluted with MeOH. The eluates were evaporated to dryness togive the title compound (Yield: 1.23 grams, MH⁺ 186).

C. 1-N-METHYL-3-PIPERIDINYLACETIC ACID ##STR146##

The mixture of compounds from Preparative Example 18A (4 grams) and 37%formalin (2.72 ml.) were hydrogenated as described in PreparativeExample 17C to give the title compound (MH⁺ 158).

PREPARATIVE EXAMPLE 19 PREPARATION OF THE R(+) AND S(-) DIASTEREOISOMERS

The racemic 8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo5,6!cyclohepta 1,2-b!pyridine prepared in Preparative Example 7C abovewas resolved by the method described in Preparative Example 15 A-C,pages 116-118, of WO 92/00293, published Jan. 9, 1992, to give the R(+)and S(-) diastereoisomers: ##STR147##

PREPARATIVE EXAMPLE 20 A. 3-BROMO-8-CHLORO-5,6-DIHYDRO-11H-BENZO5,6!CYCLOHEPTA 1,2-b!PYRIDIN-11-ONE ##STR148##

Cyclize 3- 2-(3-chlorophenyl)ethyl!-4-bromo-2-pyridine carbonitrile(10.7 g, 32.8 mmol) in triflic acid (82 mL) at 60° C. for 2 hours andthen at room temperature for 2 hours. Add 80 mL of 5N HCl carefully,then reflux in an oil bath (120° C.) for 30 minutes. Cool the solutionand pour into ice and basify with 25% NaOH solution. Extract the productwith CH₂ Cl₂ and wash with brine. Dry the organic layer with Na₂ SO₄,filter and remove the solvent to give crude product (10.4 g). Purify thecrude product with flash chromatography on silica gel and elute with 15%EtOAc-hexane to give the title compound as a white solid (9 g ,27.95mmol, Yield 85.2% MH⁺ 322).

B. 8-CHLORO-3-METHOXY-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-ONE ##STR149##

Dissolve the title compound of Preparative Example 20A (2.37g, 7.4 mmol)in dry MeOH and add Na metal (3.37g, 180 mmol). the reaction is stirredovernight at room temperature. Reflux the reaction for 3 hours, cool toroom temperature and extract with CH₂ Cl₂ -water. Dry the CH₂ Cl₂fraction and chromatograph on silica gel eluting with 50% EtOAc-hexanesto give the title compound as a light yellow solid (1.5 g, Yield 72% MH⁺274).

C. 8-CHLORO-3-METHOXY-11-(-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO5,6!-CYCLOHEPTA 1,2-b!PYRIDINE ##STR150##

By substituting in Preparative Example 2 step D,8-chloro-3-methoxy-5,6-dihydro-11H-benzo 5,6!-cyclohepta1,2-b!pyridin-11-one for 9-fluoro-5,6-dihydro-11H-benzo 5,6!-cyclohepta1,2-b!pyridin-11-one and employing basically the same methods as steps Dthrough H of Preparative Example 2, one obtains8-chloro-3-methoxy-11-(4-piperidylidene)-6,11-dihydro-5H-benzo5,6!-cyclohepta 1,2-b!pyridine as a white solid (MH⁺ 340).

PREPARATIVE EXAMPLE 25 A. ETHYL α-METHYL-4-PYRIDYL ACETIC ACID##STR151##

To dry THF at -78° C. was added diisopropylamine (5.05 g 48 mmol, 7 mL)and then n-butyl lithium. The reaction mixture was stirred for 0.5 h andthen ethyl 4-pyridyl acetic acid (7.85g, 46 mmol) was added, and afterstirring for 0.5 h at that -78° C. the reaction temperature was raisedto room temperature. DMF (20 mL was added and the reaction mixturecooled to -78° C. again. Methyl iodide (7.07 g, 50.2 mmol, 3.15 mL) wasadded and the reaction mixture stirred at that temperature for 1 h andthen at room temperature overnight. All the volatiles were then strippedoff and the reaction mixture was partitioned between water-CH₂ Cl₂. Theaqueous phase was washed twice with CH₂ Cl₂. The combined CH₂ Cl₂ phaseswere dried and evaporated. The crude product was chromatographed onsilica gel eluting with 80% EtOAc hexane to give the title compound(7.88g, MH⁺ 179).

B. α-METHYL-4-PYRIDYL ACETIC ACID ##STR152##

The compound from Preparative Example 25A was hydrolysed in a similarmanner to Preparative Example 9B to give the title compound (MH⁺ 152).

PREPARATIVE EXAMPLE 26 A.-B. α,α-DIMETHYL-4-PYRIDYL ACETIC ACID##STR153##

By essentialy the same procedure as set forth in Preparative Example10A-B, but using ethyl α-methyl-4-pyridylacetic acid (from PreparativeExample 25) instead of ethyl pyridyl acetic acid the title compound wasobtained as an oil (MH⁺ 166).

PREPARATIVE EXAMPLE 27 ETHYL 4- 4,8-DICHLORO-5,6-DIHYDRO-11H-BENZO5.6!CYCLOHEPTA 1,2-b!PYRIDIN-11-YLIDENE!-1-PIPERIDINECARBOXYLATE andETHYL 4- 2,8-DICHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-1-PIPERIDINECARBOXYLATE ##STR154##

To phosphorous oxychloride (256 mL) stirring at reflux was addeddropwise a solution of the title compound (109 grams) from Example 231Adissolved in CHCl₃ (850 mL). After stirring the resulting solution foran additional 20 minutes at reflux, the reaction mixture was cooled toroom temperature and the chloroform removed in vacuo. The resultingsolution was cooled in an ice-water bath and to it was slowly added 1Naqueous NaOH (850 mL) followed by 50% aqueous NaOH until the resultingmixture was slightly basic. Extraction with EtOAc, drying of the organicphase over anhydrous MgSO₄, concentration in vacuo, and purification byflash column chromatography provided the 4,8-dichloro product (27 grams,23% yield, mp 141.6°-145.6° C.) and the 2,8-dichloro product (9 grams,8% yield, 176.5°-177.9° C.).

PREPARATIVE EXAMPLE 28 4,8-DICHLORO-11-(4-PIPERIDYLIDENE)-6,11-5H-BENZO5,6!CYCLOHEPTA 1,2-b!PYRIDINE ##STR155##

A solution of the 4,8-dichloro compound from Preparative Example 27 (2.6grams) dissolved in absolute EtOH (50 mL) and concentrated HCl (100 mL)was stirred at reflux for 48 hours. The reaction mixture was cooled inan ice-water bath and was made basic by addition of solid KOH.Concentration in vacuo afforded a solid which was diluted with CH₂ Cl₂and water. The organic phase was dried over anhydrous MgSO₄ andconcentrated in vacuo to provide the title compound (2.0 grams, 93%yield, mp=181.1°-183.2° C.).

PREPARATIVE EXAMPLE 29 ETHYL 4- 4,8-DICHLORO-5,6-DIHYDRO-11H-BENZO5,6!CYCLOHEPTA 1,2-b!PYRIDIN-11-YLIDENE!-1-PIPERIDINE CARBOXYLATE,N-OXIDE ##STR156##

To a cooled (0° C.) solution of the 4,8-dichloro compound fromPreparative Example 27 (9.5 grams) dissolved in CH₂ Cl₂ (300 mL) underN₂ was added dropwise a solution of MCPBA (6.8 grams) dissolved in EtOAc(200 mL). The resulting mixture was washed with 1N aqueous NaOH, driedover anhydrous MgSO₄ and concentrated in vacuo. The residue was purifiedby flash column chromatography (silica gel) using 100% EtOAc then 10%MeOH-CH₂ Cl₂ to afford the title compound (4.9 grams, 50%, MH⁺ 433).

PREPARATIVE EXAMPLE 30 ETHYL 4-4-(2-AMINOETHYLTHIO)-8-CHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-1-PIPERIDINE CARBOXYLATE ##STR157##

A mixture of the title compound from Preparative Example 29 (0.53grams), 2-aminoethanethiol hydrochloride (0.74 grams) and absoluteEtOH(15 mL) was stirred at reflux for 48 hours. The mixture was cooledto 25° C., diluted with CH₂ Cl₂ and washed with 1N aqueous NaOH. Theorganic phase was dried over anhydrous MgSO₄ and concentrated in vacuoto provide the title compound (0.5 grams, 88%, MH⁺ 458).

PREPARATIVE EXAMPLE 31 1,1-DIMETHYLETHYL 2-8-CHLORO-6,11-DIHYDRO-11-(1-ETHOXYCARBONYL)-4-PIPERIDINYLIDENE!-5H-BENZO5,6!CYCLOHEPTA HEPTA 1,2-b!PYRIDIN-4-YL!THIO!ETHYL!CARBAMATE ##STR158##

To the title compound from Preparative Example 30 (0.33 grams) dissolvedin CH₂ Cl₂ (60 mL) was added di-tert-butyldicarbonate (0.17 grams). Thesolution was stirred at 25° C. under N₂ overnight. An additional 0.1grams of di-tert-butyldicarbonate was added and after 4 hours thereaction mixture was diluted with CH₂ Cl₂, washed with 1N aqueous NaOHand concentrated in vacuo to afford the title compound (0.5 grams, 100%,MH⁺ 558).

PREPARATIVE EXAMPLE 32 1,1-DIMETHYLETHYL 2- 8-CHLORO-6,11-DIHYDRO-11-4-PIPERIDINYLIDENE!-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-4-YL!THIO!ETHYL!CARBAMATE ##STR159##

To the title compound from Preparative Example 31 (0.22 grams) dissolvedin absolute EtOH (5 mL) was added water (5 mL) and solid KOH (0.33grams). The solution was stirred at reflux for 4 days, then cooled to25° C., diluted with CH₂ Cl₂ and washed with water. The organic phasewas concentrated in vacuo and the residue purified by flash columnchromatography (silica gel) using 5% MeOH-CH₂ Cl₂ saturated with NH₄ OHto afford the title compound (0.04 grams, 19%, MH⁺ 486).

PREPARATIVE EXAMPLE 33 3-PYRIDYLISOCYANATE, HYDROCHLORIDE ##STR160##

A 1.93 solution of phosgene in toluene (20%) (584 mL) was diluted withdry CH₂ Cl₂ (1 L) and the mixture was stirred at 0° C. under nitrogenatmosphere. A solution of 3-aminopyridine (21.1 grams) and dry pyridine(19 mL) dissolved in dry CH₂ Cl₂ (600 mL) was added dropwise to thestirred solution at 0° C. over a period of 5.5 hours. The mixture wasstirred at 0°-25° C. for an additional 48 hours. A stream of nitrogenwas passed through the solution to remove most of the phosgene and thesolution was then evaporated until almost all of the solvent was removedto give the title compound which was then taken up in dry pyridine (850mL) to give a stock solution of the title compound.

PREPARATIVE EXAMPLE 34 A.8-CHLORO-11-(1-ETHOXYCARBONYL-4-PIPERIDINYL)-11H-BENZO5,6!CYCLOHEPTA(1,2-b)PYRIDINE B.8-CHLORO-11-(1-ETHOXYCARBONYL-4-PIPERIDINYL)-9-ETHYL-11H-BENZO5,6!CYCLOHEPTA(1,2-b)PYRIDINE ##STR161##

The title compound of Preparative Example 1F above (51.15 grams, 0.1336mole) was dissolved in trifluoromethanesulfonic acid (170 mL). The darkmixture was heated to reflux for 70 h. The solution was cooled to roomtemperature and was then poured into 800 mL of an ice/water slurry andthe resulting mixture stirred. Concentrated NH₄ OH solution (175 mL) wasadded to the mixture in small portions so that the temperature of themixture was below 20° C. The resulting basic mixture was extracted withCH₂ Cl₂. The CH₂ Cl₂ extract was washed with brine and was thenevaporated to give a brown residue. This residue was dissolved in CH₂Cl₂ (750 mL) and the solution cooled to 0° C. Ethyl chloroformate (14.8grams, 0.136 mole) was added over 5 minutes and the resulting mixturestirred at 0° C. for 15 minutes. Saturated NaHCO₃ solution (150 mL) wasadded and the cooling bath was removed. The resulting biphasic mixturewas stirred rapidly for 3 h. The layers were separated and the CH₂ Cl₂layer was filtered through silica gel. The filtrate was evaporated todryness and the residue chromatographed on silica gel using a gradientof hexane-CH₂ Cl₂ -acetone 16:2.5:1.5 to hexane-CH₂ Cl₂ -acetone28:7.5:4.5 as eluent to give title compound A (25.02 g 49% MH⁺ 383) andtitle compound B (4.85 g, 9%, MH⁺ 411).

C. 8-CHLORO-11H-(4-PIPERIDINYL)-11H-BENZO 5,6!-CYCLOHEPTA(1,2-b)PYRIDINE##STR162##

Hydrolyze the title compound of Preparative Example 34A by dissolving in50% aqueous H₂ SO₄ (v/v) and heating to 90° to 100° C. for 16 h. Thecooled acidic mixture was neutralized with 25% NaOH solution (w/v). Theresulting mixture was extracted with EtOAc and the EtOAc extract wasdried with Na₂ SO₄. Filtration and evaporation of the EtOAc afforded thetitle compound (MH⁺ 311).

PREPARATIVE EXAMPLE 35 8-CHLORO-9-ETHYL-11-(4-PIPERIDINYL)-11H-BENZO5,6!CYCLOHEPTA 1,2-b!PYRIDINE ##STR163##

Hydrolyze the title compound of Preparative Example 34B following theprocedure described in Preparative Example 34C to provide the titlecompound. Decomposes between 205.7°-215.4° C., heating 2°-3° C. perminute.

PREPARATIVE EXAMPLE 36 A.8-CHLORO-11-(1-ETHOXYCARBONYL-4-PIPERIDINYL)-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDINE-1-OXIDE ##STR164##

The title compound from Preparative Example 34A above (20.23 grams,52.84 mmoles) was dissolved in CH₂ Cl₂ (250 mL). MCPBA (1.25equivalents) was added in one portion and this solution was stirred for45 minutes. Sodium bisulfite solution (20% w/v) was added and thebiphasic mixture rapidly stirred for 30 minutes. The layers wereseparated and the organic layer was washed with saturated Na₂ CO₃solution and dried with Na₂ SO₄. Filtration and evaporation afforded thetitle compound (21 g, 99%, mp 78.6°-89.4° C., MH⁺ 399).

B. 4,8-DICHLORO-11-(1-ETHOXYCARBONYL-4-PIPERIDINYL)-11H-BENZO5,6!CYCLOHEPTA1,2-b!PYRIDINE (A) and2,8-DICHLORO-11-(1-ETHOXYCARBONYL-4-PIPERIDINYL)-11H-BENZO5,6!CYCLOHEPTA 1,2-B!PYRIDINE (B) ##STR165##

The title compound from Preparative Example 36A (21 grams, 53 mmoles)above was dissolved in anhydrous dichloroethane (250 mL) and thesolution cooled to 0° C. POCl₃ (49.4 grams, 0.322 mole) was addeddropwise to the dichloroethane solution over 15 minutes. After the POCl₃was added the reaction mixture was warmed to 45°-50° C. and stirred for18 h. Additional POCl₃ (8.2 grams) was added and the mixture heated toreflux for 9 h. The mixture was cooled and added to an ice cooled,stirred solution of NaOH (15% w/v). The resulting biphasic mixture wasstirred rapidly for 18 h. The layers were separated and the aqueouslayer was 15 extracted with CH₂ Cl₂. The combined organic layers werewashed with water followed by brine and dried (Na₂ SO₄). The mixture wasfiltered and evaporated, and the residue chromatographed on silica gelusing a gradient of 25% EtOAc in hexane to 45% EtOAc in hexane aseluent. The title compound A was obtained as a yellow solid (5.98 g M⁺417), and title compound B was obtained as a yellow solid (1.0 g, mp84.4°-90.6° C.).

C. 4,8-DICHLORO-11-(4-PIPERIDINYL)-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDINE ##STR166##

The title compound A from Preparative Example 36B was hydrolyzed underthe conditions described in Preparative Example 34C to give the titlecompound (M⁺ 345).

PREPARATIVE EXAMPLE 37 A. 4-(8-CHLORO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE)-1-(ETHOXYCARBONYL)-PIPERIDINE ##STR167##

The preparation of the starting material for this reaction was describedin The Journal of Organic Chemistry, 1990, 55, pp. 3341-3350 byPiwinski, et al. By substituting in Preparative Example 2,8-chloro-11H-benzo 5,6!-cyclohepta 1,2-b!pyridin-11-one for9-fluoro-5,6-dihydro-11 H-benzo 5,6!-cyclohepta 1,2-b!pyridin-11-one andemploying basically the same methods as steps D through F of PreparativeExample 2, one obtains the title compound (mp 154.7°-155.5° C.).

B. 8-CHLORO-11-(4-PIPERIDINYL)-BENZO 5,6!CYCLOHEPTA 1,2-b!PYRIDINE##STR168##

Hydrolyze the title compound of Preparative Example 37A following theprocedure described in Preparative Example 334C (mp 168.5°-171.2° C.,decomposition).

PREPARATIVE EXAMPLE 38 8-CHLORO-11-(1-PIPERAZINYL)-11H-BENZO5,6!CYCLOHEPTA 1,2b!PYRIDINE ##STR169##

The preparation of the starting material for this reaction was describedin The Journal of Organic Chemistry, 1990, 55, pp. 3341-3350 byPiwinski, J. J., et al. By substituting in Preparative Example 7A,8-chloro-11H-benzo 5,6!cyclo-hepta 1,2-b!pyridin-11-one (11.53 g) (47.71mmoles) for 8-chloro-5,6-dihydro-11H-benzo 5,6!cyclohepta1,2-b!pyridin-11-one and employing basically the same methods as steps Athrough C of Preparative Example 7, one obtains 11.53 g (36%) of thetitle compound (MH⁺ 312).

PREPARATIVE EXAMPLE 39 A. ETHYL α,α-DIMETHYL-3-PYRIDYLACETIC ACIDN-OXIDE ##STR170##

By substituting in Preparative Example 8A, ethylα,α-dimethyl-3-pyridylacetic acid (4.0 g, 20.7 mmoles) for ethyl3-pyridylacetic acid and using the same method as described inPreparative Example 8A, one obtains the title compound (3.2 g, 74%, MH⁺210).

B. α,α-DIMETHYL-3-PYRIDYLACETIC ACID N-OXIDE ##STR171##

By substituting in Preparative Example 8B, ethylα,α-dimethyl-3-pyridylacetic acid N-oxide (0.142 g, 0.68 mmoles)(Preparative Example 39A) for ethyl 3-pyridylacetic acid N-oxide andusing the same method as described in Preparative Example 8B, oneobtains the title compound.

PREPARATIVE EXAMPLE 404-BROMO-8-CHLORO-11-(1-PIPERAZINYL)-6,11-DIHYDRO-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDINE ##STR172##

By substituting in Preparative Example 7A,4-bromo-8-chloro-11-(1-piperazinyl)-5,6-dihydro-11H-benzo 5,6!cyclohepta1,2-b!pyridin-11-one (1.5 g, 4.65 mmoles) (Preparative Example 20A) for8-chloro-5,6-dihydro-11H-benzo 5,6!cyclohepta 1,2-b!pyridin-11-one andusing the same methods as described in steps A through C of PreparativeExample 7, one obtains the title compound (1.31 g, 72%, MH⁺ 392).

PREPARATIVE EXAMPLE 414,8-DICHLORO-11-(1-PIPERAZINYL)-6,11-DIHYDRO-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDINE ##STR173##

By substituting in Preparative Example 7A4,8-Dichloro-5,6-dihydro-11H-benzo 5,6!cyclohepta 1,2-b!pyridin-11-one(6.64 g, 28.37 mmoles) (Preparative Example 5B) for8-chloro-5,6-dihydro-11H-benzo 5,6!cyclohepta 1,2-b!pyridin-11-one andusing the same methods as described in steps A through C of PreparativeExample 7, one obtains the title compound (2.59 g, 26%, MH⁺ 348).

PREPARATIVE EXAMPLE 42 ETHYL 4- 4-(1H-BENZOTRIAZOL-1-YL)OXY!-8-CHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-1-PIPERIDINE CARBOXYLATE ##STR174##

To a solution of the 4,8-dichloro compound from Preparative Example 27(1.5 grams) in dry DMF (20 mL) was added HOBT (1.5 grams). Afterstirring for 14 days at 25° C., NaH (0.84 grams, 60% in mineral oil) wasadded and after an additional 24 hours, the mixture was poured intowater. Filtration provided the title compound (Yield: 1.7 grams, 89%,mp=181.5°-183.9° C., MH⁺ 516).

PREPARATIVE EXAMPLE 43 ETHYL 4- 4-HYDROXY-8-CHLORO-5,6-DIHYDRO-11H-BENZO5,6!CYCLOHEPTA 1,2-b!PYRIDIN-11YLIDENE!-1-PIPERIDINE CARBOXYLATE##STR175##

To a solution of the title compound from Preparative Example 42 (0.15grams) and glacial HOAc (5 mL) was added Zn dust (0.2 grams). Afterstirring at 25° C. for 1 hour, the mixture was filtered through celiteand the filtrate concentrated in vacuo. The residue was diluted withEtOAc, washed with saturated aqueous NaHCO₃ and brine. The organic layerwas separated, added over MgSO₄ and concentrated in vacuo to give thetitle compound (Yield: 0.11 grams, 95%, MH⁺ 399).

PREPARATIVE EXAMPLE 44 ETHYL 4-3-BROMO-4-HYDROXY-8-CHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-1-PIPERIDINE CARBOXYLATE ##STR176##

To a solution of the title compound from Preparative Example 43 (1.3grams) and glacial HOAc (5 mL) was added a 0.7M bromine-HOAc solution (4mL) at 25° C. under N₂. The solution was poured into 200 mL of water andthe resulting solid was filtered, then washed with water. The solid wasdried under vacuum overnight to provide the title compound (Yield: 1.2grams, 81%, MH⁺ 477).

PREPARATIVE EXAMPLE 45 ETHYL 4-3-BROMO-4,8-DICHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-1-PIPERIDINE CARBOXYLATE ##STR177##

A mixture of the title compound from Preparative Example 44 (5.1 grams),phosphorous oxychloride (20 mL) and CHCl₃ (40 mL) was stirred at refluxover night. The reaction mixture was made basic by the snow addition of1N aqueous NaOH, and the resultant mixture was diluted with CH₂ Cl₂. Themixture was shaken well and after separation of the phases, the organicphase was washed with 1N aqueous NaOH. The organic phase was dried overanhydrous MgSO₄, filtered and concentrated in vacuo to provide a solidwhich was mixed with MeOH and filtered. Concentration of the filtrateprovided the title compound as a solid (Yield: 5.7 grams, MH⁺ 497).

PREPARATIVE EXAMPLE 463-BROMO-4,8-DICHLORO-11-(4-PIPERIDYLIDENE)-6,11-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDINE ##STR178##

A solution of the title compound from Preparative Example 45 (5.7 grams)dissolved in absolute EtOH (100 mL) and concentrated HCl (200 mL) wasstirred at reflux for 24 hours. The reaction mixture was cooled in anice-water bath and was made basic by the addition of solid KOH.Extraction with CH₂ Cl₂ and concentration of the organic phase in vacuoafforded the title compound as a solid (1.7 grams, 35% yield, MH⁺ 425).

PREPARATIVE EXAMPLE 47 A. 4-(8-CHLORO-3-NITRO-5,6-DIHYDRO-11H-BENZO5,6!CYCLOHEPTA 1,2-b!PYRIDIN-11-YLIDENE)-1-PIPERIDINE-1-CARBOXYLIC ACIDETHYL ESTER ##STR179##

Tetrabutyl ammonium nitrate (4.98 g, 16.3 mmol) was dissolved in CH₂ Cl₂(20 mL) and TFAA (3.12 g, 14.9 mmol, 2.1 mL) was then added. Thesolution was cooled to 0° C. and then added (by cannulation) to asolution of 4-(8-chloro-5,6-dihydro-11 H-benzo 5,6!-cyclohepta1,2-b!pyridin-11-ylidene)-1-piperidine-1-carboxylic aid ethyl ester(5.69 g, 14.9 mmol) in CH₂ Cl₂ (35 mL) also cooled to 0° C. The reactionmixture was stirred at 0° C. for 3 h and then allowed to go to roomtemperature (25° C.) overnight. The reaction mixture was then extractedwith saturated NaHCO₃ (60 mL) dried over MgSO₄ and concentrated to givea semi-solid material that was chromatographed on silica gel elutingfirst with 10% and then 20% EtOAc-hexane. Removal of the organicsolvents gave the title compound in 44% yield as a light yellow solid.MP=90.4°-91.0° C., MH⁺ 428.

B. 4-(8-CHLORO-3-AMINO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE)-1-PIPERIDINE-1-CARBOXYLIC ACID ETHYL ESTER##STR180##

The title compound from Preparative Example 47A (5.99 g, 14 mmol) wasdissolved in 85% aqueous EtOH. To this solution was added iron filings(7.01 g, 125.57 mmol) and CaCl₂ (0.69 g, 6.29 mmol) and the reactionmixture was refluxed for 16 h. The reaction mixture was filtered througha bed of celite while hot and the celite was washed with hot EtOH (700mL). The EtOH solution was then decolorized with activated charcoal (2.4g) and then filtered through celite. EtOH was then rotary eavaporated togive the title compound in 100% yield as an off-white solid.MP=102.4°-103.1° C., MH⁺ 398.

C. 4-(8-CHLORO-3-BROMO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE)-1-PIPERIDINE-1-CARBOXYLIC ACID ETHYL ESTER##STR181##

The title compound from Preparative Example 47B (3.00 g, 7.60 mmol) wasdissolved in HBr (48%, 30 mL). The reaction mixture was cooled to -5° C.(ice-ethylene glycol bath) and bromine (2 mL) was added dropwise. Thereaction mixture was stirred at -5° C. for 15 minutes. Sodium nitrite(1.57 g, 22.8 mmol) dissolved in water (15 mL) was slowly added to thereaction mixture. The reaction mixture was then stirred for 45 minutesand then quenched with 40% NaOH to pH˜10. The aqueous phase was thenextracted with EtOAc (3×100 mL). Combined EtOAc fractions were driedover Na₂ SO₄ and then concentrated to give the title compound in 83%yield as a light brown solid. Mp=146°-148° C., MH+ 463.

PREPARATIVE EXAMPLE 48

Step A: ##STR182##

Combine 6 g (15.11 mmol) of the title compound of Preparative Example47B and benzene, and add 2.3 g (9.06 mmol) of iodine. Heat the mixtureat reflux for 3 hours, cool, then dilute with 50 mL of CH₂ Cl₂. Wash theorganic phase with 5% NaHSO₃ (aqeuous) (3×80 mL), then with 1M NaOH(aqueous) (2×80 mL), and dry over MgSO₄. Concentrate to a residuechromatograph (silica gel, 30% EtOAc/hexanes), to give 3.2 g (42% yield)of the product iodo compound. Mass Spec., MH+=509

Step B: ##STR183##

The product of Step A is hydrolyzed via substantially the same procedureas described in Example 358, Step A, to give the iodoamine product in89% yield.

PREPARATIVE EXAMPLE 49 ##STR184##

The product of Preparative Example 47, Step C, (2.42 g) is hydrolyzedvia substantially the same procedure as described in Example 358, StepA, to give 1.39 g (69% yield) of the bromoamine product.

Using the starting compound indicated and following essentially the sameprocedure as for Preparative Example 49, the following compounds wereprepared:

    ______________________________________                                        Starting                         Ana-                                         Com-                             lytical                                      pound  Compound                  Data                                         ______________________________________                                        Prepara- tive Example 51, Step C                                                      ##STR185##               Mass Spec.: MH.sup.+  = 407                         Preparative Example 49A                                                ______________________________________                                    

PREPARATIVE EXAMPLE 50 ##STR186## Step A: ##STR187##

Combine 82.0 g (0.26 mole) of the product of Preparative Example 1, StepG, and 1 L of toluene, then add 20.06 g (0.53 mole) of LiAIH₄ and heatthe reaction mixture at reflux overnight. Cool the mixture to roomtemperature and add ˜1 L of Et₂ O, followed by dropwise addition ofsaturated Na₂ SO₄ (aqueous) until a precipitate forms. Filter and stirthe filtrate over MgSO₄ for 30 minutes, then concentrate in vacuo togive the product compound in 83% yield. Mass Spec.: MH⁺ =313

Step B: ##STR188##

Combine 74 g (0.24 mol) of the Product from Step A and 95 g (6.84equiv.) of HCO₂ H, then add 129 g of 7% formadehyde and heat the mixtureto ˜80° C. for 2 hours. Cool the mixture to room temperature and basifywith 25% NaOH (aqueous). Extract with EtOAc (3×1.3 L), dry the extractsover Na₂ SO₄ and concentrate to a residue. Recystallize the residue fromiPr₂ O and Et₂ O to give the product compound. Mass Spec.: MH⁺ =326.

Step C: ##STR189##

Combine 28 g of the Product of Step B and 800 mL of THF and cool to -65°C. Add a solution of 41.2 mL (1.2 equiv.) of 2.5M n-BuLi in hexanes,stir for 1 hour at -65° C., then warm to -30° C. and stirred at thattemperature for 1 hour. Cool to -65° C. and add 10.5 mL of CH₃ I, thenwarm to -10° C. and quench with 1.5 mL of Et₂ O followed by 10 mL of NH₄OH (aqueous). Dry the organic phase over K₂ CO₃ and concentrate in vacuoto a residue. Dissolve the residue in CH₂ Cl₂, wash with H₂ O, dry overNa₂ SO₄ and concentrate in vacuo to give a residue. Chromatograph(silica gel, 5% MeOH/EtOAc+NH₄ OH) to give 26 g of the product compound.

Step D: ##STR190##

Combine 26 g of the Product of Step C, toluene, and 33 mL (3 equiv.) ofEt₃ N, then heat to 70° C. Slowly add 45 mL (6 equiv.) of ClCO₂ Et overa period of 45 min. Stir for 15 min. then pour the mixture into ice andadd 100 mL of 1N NaOH (aqueous). Extract with EtOAc, dry the extract andconcentrate in vacuo to give 37 g of the product compound.

Step E: ##STR191##

Hydrolyze 3.5 g (8.8 mmol) of the Product of Step D, by substantiallythe same procedure as described for Example 358, Step A, to give 2.26 g(79% yield) of the product compound. Mass Spec.: MH⁺ =327

PREPARATIVE EXAMPLE 51

Step A: ##STR192##

Dissolve 8.66 g (28.6 mmol) of tetra-n-butylammonium nitrate in 50 mL ofCH₂ Cl₂ and add 5.99 g (28.57 mmol, 2.1 mL) of TFAA. Cool to 0° C. andadd the mixture (via cannula) to a solution of 10.36 g (14.9 mmol) ofthe product of Preparative Example 50, Step D in 150 mL of CH₂ Cl₂ at 0°C., then stir at 0° C. for 3 hours. Allow the mixture to warm to 25° C.while stirring overnight, then extract with 150 mL of saturated NaHCO₃(aqueous) and dry over MgSO₄. Concentrate in vacuo to a residue andchromatograph the residue (silica gel, 10% EtOc/hexane, then 20%EtOAc/hexane) to give a 57% yield of the product compound. Mass Spec.:MH⁺ =442.

Step B: ##STR193##

Combine 5.9 g (13.29 mmol) of the Product of Step A and 400 mL of 85%EtOH (aqueous), add 6.6 g (119 mmol) of Fe filings and 0.66 g (5.98mmol) of CaCl₂, and heat at reflux for 16 hours. Filter the hot mixturethrough a bed of celite®, wash the celite® with 700 mL of hot EtOH.Concentrate the filtrate in vacuo to give a 100% yield of the productcompound. Mass Spec.: MH⁺ =414.

Step C: ##STR194##

Combine 6.5 g (15.7 mmol) of the Product of Step B and 63 mL of 48% HBr,cool the mixture to -5° C. and slowly (dropwise) add 4.4 mL of Br₂bromine (4.4 mL). Stir the mixture at -5° C. for 15 minutes and slowlyadd a solution of 3.25 g (47.1 mmol) of NaNO₂ in 30 mL of water. Stirfor 45 minutes, then quench with 50% NaOH (aqueous) to pH˜10. Extractwith EtOAc (3×200 mL), dry the combined extracts over Na₂ SO₄ andconcentrate in vacuo to give 6.32 g (81% yield) of the product compound.Mass Spec.: MH⁺ =479

PREPARATIVE EXAMPLE 51A ##STR195## Step A: ##STR196##

Combine 24.32 g (74.9 mmol) of the Product from Preparative Example 50,Step A, 500 mL of toulene, 83 mL of Et₃ N and 65.9 mL of ethylchloroformate and heat the mixture at reflux overnight. Cool to 25° C.,pour into 200 mL of water and extract with EtOAc, Dry the extract overMgSO₄, concentrate in vacuo to a residue and chromatograph (silica gel,50% EtOAc/hexane) to give 15 g of the product compound. Mass Spec.: MH⁺=385.

Step B: ##STR197##

Dissolve 3.2 g (10.51 mmol) of tetra-n-butylammonium nitrate in 25 mL ofCH₂ Cl₂ and add 2.2 g (10.51 mmol, 1.5 mL) of TFAA. Cool to 0° C. andadd the mixture (via cannula) to a solution of 3.68 g (9.56 mmol) of theproduct of Step A in 50 mL of CH₂ Cl₂ at 0° C., then stir at 0° C. for 3hours. Allow the mixture to warm to 25° C. while stirring overnight,then extract with saturated NaHCO₃ (aqueous) and dry over MgSO₄.Concentrate in vacuo to a residue and chromatograph (silica gel, 30%EtOc/hexane) to give a 1.2 g of the product compound. Mass Spec.: MH⁺=430.

Step C: ##STR198##

Combine 2.0 g (4.7 mmol) of the Product of Step B and 150 mL of 85% EtOH(aqueous), add 2.4 g (42 mmol) of Fe filings and 0.24 g (2.1 retool) ofCaCl₂, and heat at reflux for 16 hours. Filter the hot mixture through abed of celite®, wash the celite® with hot EtOH. Concentrate the filtratein vacuo to give a 100% yield of the product compound. Mass Spec.: MH⁺=400.

Step D: ##STR199##

Combine 2.0 g (5.2 mmol) of the Product of Step C and 20 mL of 48% HBr,cool the mixture to -5° C. Stir the mixture at -5° C. for 15 minutes andslowly add a solution of 1.07 g (15.5 mmol) of NaNO₂ in 10 mL of water.Stir for 45 minutes, then quench with 50% NaOH (aqueous) to pH˜10.Extract with EtOAc, dry the combined extracts over MgSO₄ and concentratein vacuo to give the product compound. Mass Spec.: MH⁺ =465

Step E: ##STR200##

Hydroyze 4.0 g of the Product of Step D via substantially the sameprocess as described for Example 358, Step A, to give 1.39 g of theproduct compound. Mass Spec.: MH⁺ =392

PREPARATIVE EXAMPLE 52 ##STR201## Step A: ##STR202##

Dissolve 9.8 g (30.2 mmol) of the Product of Preparative Example 1, StepE, in THF under nitrogen, cool the mixture to -15° C., then add 17.76 mL(30.3 mmol) of 2.5M n-butyllithium in hexanes and stir for 1.5 hours.Cool the reaction mixture to -70° C. and add 2.45 mL (60 mmol) of MeOHand warm to room temperature overnight. Add 300 mL of (Et₂ O) andextract with water (3×100 mL). Dry the extracts, concentrate in vacuo toa residue and chromatograph the residue (silica gel, 5% Et₃ N/EtOAc) togive 6.59 g (68% yeild) of the product compound.

Via substantially the same procedure as described in Preparative Example52, Step A, except that methyl iodide is used in place of MeOH, thefollowing product compound is prepared:

    ______________________________________                                        Starting                       Analytical                                     Compound                                                                              Compound               Data                                           ______________________________________                                        Preparative Example 1, Step E                                                          ##STR203##            Mass Spec.: MH.sup.+  = 339                            Preparative Example 52A                                               ______________________________________                                    

Step B: ##STR204##

Treat 3 g (9.23 mmol) of the Product of Step A with 10 mL of ClCO₂ Etand 10 mL of Et₃ N via substantially the same procedure as described inPreparative Example 50, Step D, to give 2.2 g (64% yield) of the productcompound. Mass Spec.: MH⁺ =383

Using the starting compound indicated and substantially the sameprocedure as described in Preparative Example 52, Step B, the followingproduct compound is prepared:

    ______________________________________                                        Starting                       Analytical                                     Compound                                                                              Compound               Data                                           ______________________________________                                        Preparative Example 52A, Step E                                                        ##STR205##            Mass Spec.: MH.sup.+  = 397                            Preparative Example 52A                                               ______________________________________                                    

Step C: ##STR206##

Treat the Product of Step B via substantially the same procedure asdescribed in Preparative Example 1, Step F, to give the productcompound. Mass Spec.: MH⁺ =310

Using the starting compound indicated and substantially the sameprocedure as described in Preparative Example 52, Step C, the followingproduct compound is prepared:

    ______________________________________                                        Starting                       Analytical                                     Compound                                                                              Compound               Data                                           ______________________________________                                        Preparative Example 52A, Step B                                                        ##STR207##            Mass Spec.: MH.sup.+  = 325                            Preparative Example 52A                                               ______________________________________                                    

PREPARATIVE EXAMPLE 53 ##STR208## Step A: ##STR209##

Combine 14.95 g (39 mmol) of the Product of Preparative Example 34A and150 mL of CH₂ Cl₂, then add 13.07 g (42.9 mmol) of (nBu)₄ NNO₃ and coolthe mixture to 0° C. Slowly add (dropwise) a solution of 6.09 mL (42.9mmol) of TFAA in 20 mL of CH₂ Cl₂ over 1.5 hours. Keep the mixture at 0°C. overnight, then wash successively with saturated NaHCO₃ (aqueous),water and brine. Dry the organic solution over Na₂ SO₄, concentrate invacuo to a residue and chromatograph the residue (silica gel,EtOAc/hexane gradient) to give 4.32 g and 1.90 g of the two productcompounds 53(i) and 53(ii), respectively.

Mass Spec. for compound 53(i): MH⁺ =428.2;

Mass Spec. for compound 53(ii): MH⁺ =428.3

Step B: ##STR210##

The compound 53(ii) from Step A (0.20 g) is hydrolyzed via substantiallythe same procedure as described for Example 356, Step A, to give 0.16 gof the product compound.

Using the starting compound indicated and substantially the sameprocedure as described in Preparative Example 53, Step B, the followingproduct compound is prepared:

    ______________________________________                                        Starting                         Ana-                                         Com-                             lytical                                      pound  Compound                  Data                                         ______________________________________                                        Prepara- tive Example 53, Step A, com- pound 53(i)                                    ##STR211##               --                                                  Preparative Example 53A                                                Prepara- tive Example 54, Step B, com- pound 54(ii)                                   ##STR212##               Mass Spec.: MH.sup.+  = 466.9                       Preparative Example 53B                                                Prepara- tive Example 54, Step B, com- pound 54(i)                                    ##STR213##               Mass Spec.: MH.sup.+  = 466.9                       Preparative Example 53C                                                ______________________________________                                    

PREPARATIVE EXAMPLE 54

Step A: ##STR214##

Combine 22.0 g (51.4 mmol) of the product 53(i) from Preparation 53,Step A, 150 mL of 85% EtOH (aqueous), 25.85 g (0.463 mole) of Fe powderand 2.42 g (21.8 mmol) of CaCl₂, and heat at reflux overnight. Add 12.4g (0.222 mole) of Fe powder and 1.2 g (10.8 mmol) of CaCl₂ and heat atreflux for 2 hours. Add another 12.4 g (0.222 mole) of Fe powder and 1.2g (10.8 mmol) of CaCl₂ and heat at reflux for 2 hours more. Filter thehot mixture through celite®, wash the celite® with 50 mL of hot EtOH andconcentrate the filtrate in vacuo to a residue. Add 100 mL of anhydrousEtOH, concentrate to a residue and chromatograph the residue (silicagel, MeOH/CH₂ Cl₂ gradient) to give 16.47 g of the product compound.

Step B: ##STR215##

Combine16.47 g (41.4 mmol) of the product compound from PreparativeExample 54, Step A, and 150 mL of 48% HBr (aqueous) and cool to -3° C.Slowly add (dropwise) 18 mL of bromine, then slowly add (dropwise) asolution of 8.55 g (0.124 mole) of NaNO₃ in 85 mL of water. Stir for 45minutes at -3° to 0° C., then adjust to pH=10 by adding 50% NaOH(aqueous). Extract with EtOAc, wash the extracts with brine and dry theextracts over Na₂ SO₄. Concentrate to a residue and chromatograph(silica gel, EtOAc/hexane gradient) to give 10.6 g and 3.28 g of the twoproduct compounds 54(i) and 54(ii), respectively.

Mass Spec. for compound 54(i): MH⁺ =461.2;

Mass Spec. for compound 54(ii): MH⁺ =539

PREPARATIVE EXAMPLE 55 ##STR216##

The title compound is known and is prepared by the procedure describedin Bioorg. & Med. Chem. Lett., 3, (No. 6) 1073-1078 (1993).

PREPARATIVE EXAMPLE 56 ##STR217## Step A: ##STR218##

Combine 2.04 g of the product of Preparative Example 44, 1.3 mL of PBr₃,1.0 mL of Et₃ N and 20 mL of CH₂ Br₂, and heat the mixture at refluxovernight. Cool the mixture, dilute with CH₂ Cl₂ and wash with 1N NaOH(aqueous). Dry over MgSO₄ and concentrate in vacuo to give 1.22 g (53%yield) of the product compound. Mass Spec.: MH⁺ =541

Step B: ##STR219##

Combine 0.3 g of the product compound from Preparative Example 56, StepA, and 8 mL of n-butylamine and stir at 120° C. in a sealed tube for 48hours. Concentrate in vacuo to a residue and purify by preparative platechromatography (silica gel, 1.5-2.5% MeOH/CH₂ Cl₂) to give 80 mg (27%)yield of the product compound. Mass Spec.: MH⁺ =534

Step C: ##STR220##

Combine 66 mg of the product compound from Preparative Example 56, StepB, 4 mL of anhydrous EtOH, and 15 mL of concentrated HCl stir at refluxfor 60 hours. Cool the reaction mixture to about 0° C. and basify by theadding KOH. Extract with CH₂ Cl₂, dry the extract over MgSO₄, andconcentrate in vacuo to give 46 mg (81% yield) of the product compound.Mass Spec.: MH⁺ =462

PREPARATIVE EXAMPLE 57 ##STR221## Step A: ##STR222##

Combine 1.19 g of the product of Preparative Example 44, 10 mL ofanhydrous DMF, 0.2 g of NaH (60% in mineral oil) and 0.19 mL of methyliodide, and stirr at room temperature overnight. Concentrate in vacuo toa residue, dilute the residue with CH₂ Cl₂, wash with saturated NaHCO₃(aqueous), and dry over MgSO₄. Concentrate in vacuo to give 1.13 g (92%yield) of the product compound. Mass Spec.: MH⁺ =493.

Step B: ##STR223##

Hydrolyze 1.13 g of the product of Step A via substantially the sameprocedure as describe for Preparative Example 56, Step C, to give 0.61 g(63% yield) of the product compound.

PREPARATIVE EXAMPLE 58 ##STR224## Step A: ##STR225##

Combine 1.07 g (3.52 mmol) of tetrabutylammonium nitrate, 4 mL ofanhydrous CH₂ Cl₂ and 0.743 g (3.52 mmol) of TFAA, and add the resultingmixture to a solution of 1.22 g (3.20 mmol) of the title compound ofPreparative Example 37 in 8 mL of anhydrous CH₂ Cl₂ at room temperature.Stir at room temperature overnight, then wash with 20 mL of saturatedNaHCO₃ (aqueous) and 20 mL of brine, and dry over MgSO₄. Concentrate invacuo and chromatograph the resulting residue (silica gel, EtOAc/hexane)to give 0.216 g of the product compound 58(i) and 0.27 g of the productcompound 58(ii).

Analytical data for Compound 58(i): Mass Spec. MH⁺ =426.

Analytical data for Compound 58(i): m.p. 97.5°-99.2° C.

Step B: ##STR226##

Reduce the product 58(i) from Step A via essentially the same procedureas described in Preparative Example 47, Step B, to give the productcompound. Mass Spec.: MH⁺ =396

Step C: ##STR227##

React the product from Step B with HBr and bromine via essentially thesame procedure as described in Preparative Example 47, Step C, to givethe product compound. Mass Spec.: MH⁺ =459

Step D: ##STR228##

Hydrolyze 0.83 g of the product from Step C via essentially the sameprocedure as described in Preparative Example 56, Step C, to give 0.56 gof the product compound. Mass Spec.: MH⁺ =387

PREPARATIVE EXAMPLE 59 ##STR229## Step A: ##STR230##

Combine 7.3 g (26.4 mmol) of the starting ketone (see J. Med. Chem.,4238 (1992)) and 230 mL of THF and cool to 0° C. Add a solution of 32.2mmol) of N-methyl-piperidine-4-magnesium bromide in 26 mL of THF andstir at 0°-5° C. for 4 hours. Add 400 mL of EtOAc, wash with saturatedNH₄ Cl (aqueous), and dry over MgSO₄. Concentrate in vacuo to a residue,add ˜200 mL of CH₂ Cl₂ and stir for 0.5 hours. Filter to collect theresulting solid and concentrate the filtrate to a volume of ˜100 mL andlet sit at 5° C. for 18 hours. Filter and combine the solids to obtain atotal of 7 g (19.4 mmol) of the product compound. m.p.=153.7°-158° C.;Mass Spec.: (CI) MH⁺ =376

Step B: ##STR231##

Combine 5 g of the product from Step A and 30 mL of TFA at ambienttemperature and stir for 1 hour. Concentrate in vacuo to a residue,dissolve the residue in CH₂ Cl₂ and wash with a saturated NaHCO₃(aqueous). Concentrate in vacuo to give 4.64 g of the product compound.m.p.=136.7°-138° C.; Mass Spec.: (FAB) MH⁺ =358.1

Step C: ##STR232##

Combine 0.6 g (1.75 mmol) of the product of Step B and 25 mL of toluene,add 0.73 mL (5.27 mmol) of Et₃ N and 1.34 mL (14 mmol) of ClCO₂ Et, andheat to 80° C. for 2 hours. Add 0.7 mL more of ClCO₂ Et, heat for 1 morehour, then cool to 25° C. and concentrate in vacuo to a residue.Dissolve the residue in EtOAc and wash with 1N NaOH (aqueous) followedby brine. Dry over MgSO₄, concentrate in vacuo to a residue andchromatograph (silica gel, 10% EtOAc/hexanes) to give 0.55 g of theproduct compound. Mass Spec.: (FAB) MH⁺ =416.2

Step D: ##STR233##

Dissolve 5 g (12.5 mmol) of the product of Step C in 30% HBr in HOAc andheat at 40° C. for 24 hours, then cautiously add the mixture to cold 25% NaOH (aqueous). Extract with CH₂ Cl₂ (3×100 mL), concentrate theextracts to a residue and chromatograph (silica gel, 5% to 30% MeOH/CH₂Cl₂) to give 2.18 g of the product compound. m.p.=159.5°-160.8° C.; MassSpec.: (FAB) MH⁺ =344.1

PREPARATIVE EXAMPLE 60 ##STR234## Step A: ##STR235##

Combine 16.25 g (40.83 mmol) of the product of Preparative Example 47,Step B, and a slurry of 7.14 g (61.11 mmol) of NOBF₄ in 100 mL of CH₂Cl₂ and stir the mixture for 3 hours. Add 100 mL of o-dichlorobenzeneand heat for 5 hours, distilling the CH₂ Cl₂ from the mixture.Concentrate in vacuo to a residue, add 200 mL of CH₂ Cl₂ and wash withwater (2×200 mL). Dry over MgSO₄, concentrate in vacuo to a residue, andchromatograph (silica gel, 20% EtOAc/hexane) to give 4.1 g of productcompound 60(i) and 4.01 g of Product compound 60(ii).

Analytical data for compound 60(i): Mass Spec.: MH⁺ =418

Analytical data for compound 60(ii): Mass Spec.: MH⁺ =401

Step B: ##STR236##

Hydrolyze 3.4 g of the product 60(ii) from Step A via essentially thesame process as described for Example 358, Step A, to give 3.01 g ofproduct compound. Mass Spec.: MH⁺ =329

Using the starting compound indicated and substantially the sameprocedure as described in Preparative Example 60, Step B, the followingproduct compound is prepared:

    ______________________________________                                        Starting                         Ana-                                         Com-                             lytical                                      pound  Compound                  Data                                         ______________________________________                                        Prepara- tive Example 60, Step A, com- pound 60(i)                                    ##STR237##               Mass Spec.: MH.sup.+  = 346                         Preparative Example 60A                                                ______________________________________                                    

PREPARATIVE EXAMPLE 61 ##STR238## Step A: ##STR239##

Combine 10 g (60.5 mmol) of ethyl 4-pyridylacetate and 120 mL of dry CH₂Cl₂ at -20° C., add 10.45 g (60.5 mmol) of MCPBA and stir at -20° C. for1 hour and then at 25° C. for 67 hours. Add an additional 3.48 g (20.2mmoles) of MCPBA and stir at 25° C. for 24 hours. Dilute with CH₂ Cl₂and wash with saturated NaHCO₃ (aqueous) and then water. Dry over MgSO₄,concentrate in vacuo to a residue, and chromatograph (silica gel,2%-5.5% (10% NH₄ OH in MeOH)/CH₂ Cl₂) to give 8.12 g of the productcompound. Mass Spec.: MH⁺ =182.15

Step B: ##STR240##

Combine 3.5 g (19.3 mmol) of the product of Step A, 17.5 mL of EtOH and96.6 mL of 10% NaOH (aqueous) and heat the mixture at 67° C. for 2hours. Add 2N HCl (aqueous) to adjust to pH=2.37 and concentrate invacuo to a residue. Add 200 mL of dry EtOH, filter through celite® andwash the filter cake with dry EtOH (2×50 ml). Concentrate the combinedfiltrates in vacuo to give 2.43 g of the title compound.

Using the product of Preparative Example 26 and substantially the sameprocedure as described for Preparative Example 61, Steps A and B, thefollowing compound was prepared: ##STR241##

PREPARATIVE EXAMPLE 62 ##STR242##

Combine 10 g (65.7 mmol) of 3-methoxycarbonylaminopyridine and 150 mL ofCH₂ Cl₂, cool to 0° C. and slowly add (dropwise) a solution of 13.61 g(78.84 mmol) of MCPBA in 120 mL of CH₂ Cl₂ at 0° C. over a period of 1hour. Stir the mixture at 25° C. for 5 days, then wash with saturatedNaHCO₃ (aqueous), then water and dry over MgSO₄. Concentrate in vacuo toa residue and chromatograph (silica gel, 2%-5% (10% NH₄ OH in MeOH)/CH₂Cl₂) to give the product compound. Mass Spec.: MH⁺ =169

PREPARATIVE EXAMPLE 63 ##STR243##

Combine 5 g (36.0 mmol) of isonicotinic acid 1-N-oxide and 150 mL ofanhydrous DMF, add 5.5 mL (39.6 mmol) of Et₃ N and stir at 0° C. for 0.5hours. Slowly add (dropwise) 8.5 mL (39.6 mmol) of diphenylphosphorylazide at 0° C. over 10 minutes, stir at 0° C. for 1 hour and then at 25°C. for 24 hours (as generally described in Pavia, et al., Journal ofMedicinal Chemistry, 33, 854-861 (1990). Concentrate in vacuo to aresidue and chromatograph (silica gel, 0.5%-1% MeOH/CH₂ Cl₂) to give 5.9g of the product compound.

Using nicotinic acid 1-N-oxide and substantially the same procedure asdescribed for Preparative Example 63 the following compound wasprepared: ##STR244##

PREPARATIVE EXAMPLE 64

Step A: ##STR245##

Hydrogenate 25 g (144 mmol) of 3-pyridylacetic acid hydrochloride for144 hours using the procedure described in Preparative Example 15 togive 20 g of the product compound. Mass Spec.: MH⁺ =144.

Step B: ##STR246##

React 12 g (83.8 mmol) of the product of Step B for 148 hours using theprocedure described in Preparative Example 13, Step B, to give 17.5 g ofthe product compound. Mass Spec.: MH⁺ =244.25

PREPARATIVE EXAMPLE 65 ##STR247##

Combine 25 g (164.4 mmol) of methyl 3-pyridylcarbamate and 163.3 mL of1N HCl (aqueous), stir until all of the solid dissolves, thenhydrogenate over 10% Pd/C at 25° C. at 55 psi for 220 hours. Filter,wash the solids with water and treat the combined filtrates with 150 mLof BioRad AG1X8 ion exchange resin (OH⁻). Filter, wash the resin withwater and concentrate the filtrate to a volume of 100 mL. Add 16.43 mL(197.3 mmol) of 37% formalin and hydrogenate over 10% Pd/C at 25° C. at55 psi for 89 hours. Filter, wash the solids with water and concentratein vacuo to give 24.3 g of the title compound. Mass Spec.: MH⁺ =173.2

PREPARATIVE EXAMPLE 66 ##STR248##

Cool 50.0 g (20.5 mmol) of 8-chloro-5,6-dihydro-11H-benzo 5,6!cyclohepta1,2-b!pyridin-11-one to 0° C., slowly add 75 mL (93.69 mmol) of sulfurmonochloride over 20 minutes, then slowly add 25 mL (48.59 mmol) of Br₂over 15. Heat at 95° C. for 20 hour, add 12.5 mL (24.3 mmol) of Br₂ andheat for a another 24 hours. Cool the mixture, and slowly add to amixture of CH₂ Cl₂ and 1N NaOH (aqueous) at 0° C. Wash the organic phasewith water, dry over MgSO₄ and concentrate in vacuo to a residue.Chromatograph the residue (silica gel, 500 mL CH₂ Cl₂ then 0.2%-5% (10%NH₄ OH in MeOH)/CH₂ Cl₂), then chromatograph again (silica gel, 3%-8.5%EtOAc/hexane) to give 8.66 g of the product compound. Mass Spec.: MH⁺=322

PREPARATIVE EXAMPLE 67 ##STR249##

Dissolve 0.16 g (0.46 mmol) of 4-(8-methyl-5,6-dihydro-11H-benzo5,6!cyclohepta 1,2-b!pyridin-11-ylidine)-1-ethoxycarbonylpiperidine, in2 mL EtOH and add 4 mL of 12N HCl. Heat the solution for 3 hours at 85°C., then cool to 25° C. Adjust to pH=10 with 50% NaOH (aqueous) andextract several times with 50 mL of EtOAc. Combine the organic layers,dry them over MgSO₄, and concentrate in vacuo to give the productcompound.

PREPARATIVE EXAMPLE 68 ##STR250## Step A: ##STR251##

Dissolve 2 g (5.22 mmol) of the title compound of Preparative Example 1Fin 2.6 mL of dry N-methyl-2-pyridone. Add 0.87 g (9.4 mmol) of CuCN and0.139 g (0.93 mmol) of sodium iodide. Heat the mixture at 200° C. undernitrogen for 20 hours, cool to 25° C. and repeatedly grind and mix withfive 50 mL portions of CH₂ Cl₂ and 7M NH₄ OH (aqueous). Wash the organiclayer with 7M NH₄ OH until the organic layer is no longer blue or green.Dry the combined organic layers over MgSO₄ and concentrate in vacuo to aresidue. Chromatograph (silica gel 70% EtOAc/hexane), then recrystallizefrom EtOAc/hexane to give the product compound. m.p.=152.4°-153.5° C.;Mass Spec.: MH⁺ =374

Step B: ##STR252##

Dissolve 4.08 g (10.93 mmol) of the product of Step A in 12M HCl andheat at 85° C. for 18 hours. Concentrate in vacuo to a residue. Dissolvethe residue in 175 mL of MeOH, saturate with HCl gas, and heat at refluxfor 18 hours. Concentrate in vacuo to give the product compound as itsHCl salt. Mass Spec.: MH⁺ =335

PREPARATIVE EXAMPLE 68 ##STR253##

Combine 75 g (0.196 mole) of the Product of Example 1, Step F, and 300mL of CH₂ Cl₂ at 0° C., and slowly add (dropwise) a solution of 72 g(0.236 mole) of tetrabutylammonium nitrate and 35 mL (0.247 mole) ofTFAA in 500 mL of CH₂ Cl₂. Stir at 25° C. overnight, slowly add(dropwise) 1 L of saturated NaHCO₃ (aqueous). Separate the layers, washthe organic phase with brine and dry over MgSO₄. Concentrate in vacuo toa residue, chromatograph twice (1 kg silica gel, gradient of EtOAc/CH₂Cl₂) to give 8.63 g of product compound 69(i), and 34 g of productcompound (ii). Recrystallize compound 69(i) from CH₂ Cl₂ /hexane to givethe purified product compound 69(i). m.p.=186°-187° C.; Mass Spec.:(FAB) MH⁺ =401

PREPARATIVE EXAMPLE 69 ##STR254##

Combine 0.4 g (1 mmol) of the Product of Example 47, Step B, and 0.2 mL(1.2 mmoles) of 2, 5-diethoxytetrahydrofuran in 3 mL of glacial HOAc,and heat at reflux for 1.5 hours. Cool the mixture, wash with saturatedNaHCO₃ (aqueous), then with brine, dry over MgSO₄, and concentrate invacuo to a residue. Chromatograph (silica gel, 5%-15% EtOAc/CH₂ Cl₂) togive 0.34 g of the product compound. Mass Spec.: (FAB) MH⁺ =448

PREPARATIVE EXAMPLE 70 ##STR255## Step A: ##STR256##

Combine 13.8 g (34.7 mmol) of the Product of Example 47, Step B, and 90mL of water at 0° C., add a solution of 6.9 mL of concentrated H₂ SO₄ in45 mL of water and stir the mixture. Slowly add (dropwise) a solution of2.55 g (40 mmol) of NaNO₂ in 75 mL of water and stir at 0°-5° C. for 0.5hours. Add a boiling solution of 35.1 g CuSO₄ in 135 mL of water andheat at 100° C. for 15 min. Cool the mixture, extract with CH₂ Cl₂(2×200 mL), wash the extracts with brine, dry over MgSO₄, andconcentrate in vacuo to a residue. Chromatograph (silica gel, 1.5%-10%MeOH/CH₂ Cl₂) to give 11.36 g of the product compound.

Step B: ##STR257##

Combine 11.36 g (28.5 mmol) of the Product of Step A and 12.4 g (34.7mmol) of N-phenyltriflimide in 120 mL of dry CH₂ Cl₂ at 0° C., add 4.6mL (33 mmol) of Et₃ N and stir at 25° C. overnight. Concentrate in vacuoto a residue and chromatograph (silica gel, 2%-5% EtOAc/CH₂ Cl₂) to give10.95 g of the product compound. Recrystallize from hot MeOH.m.p.=154.5°-156° C.; Mass Spec.: (FAB) MH⁺ =531

Step C: ##STR258##

Combine 12.2 g (23 mmol) of the Product of Step B and 85 mL of1-methyl-2-pyrrolidinone at 25° C., then add 2.84 g LiCl, 0.212 g oftrisfurylphosphine and 0.585 g of dipalladiumtribenzylideneacetone andstir for 15 min. Slowly add (dropwise) 7.5 mL (25.77 mmol) oftributylvinyltin and stir at 25° C. for 2.5 hours. Dilute with 500 mL ofwater at 0° C. and extract with 6700 mL of EtOAc. Filter the organicphase through celite®, wash the celite with EtOAc, then wash thefiltrate twice with 30% NaF (aqueous). Filter the organic solution washwith brine and dry over MgSO₄. Concentrate in vacuo to a residue andchromatograph (silica gel, 15%-40% EtOAc/hexane) to give 8.58 g of theproduct compound. Mass Spec.: (FAB) MH⁺ =409

Using the stannane indicated, the following compounds were prepared viasubstantially the same procedure as described for Preparative Example70, Step C:

    __________________________________________________________________________    Starting Compound                                                                         Product Compound         Analytical Data                          __________________________________________________________________________    2-(tributylstannyl)- thiophene and Preparative Example 70 Step                             ##STR259##              m.p. = 155°˜157°                                          C. Mass Spec.: MH.sup.+  = 465                       Preparative Example 70-A                                          __________________________________________________________________________

Step D: ##STR260##

Hydrolyze 1.18 g (2.89 mmol) of the product of Step C via substantiallythe same procedure as described in Example 358, Step A, to give 0.95 gof the product compound. Mass Spec.: (FAB) MH⁺ =337

PREPARATIVE EXAMPLE 71 ##STR261## Step A: ##STR262##

Combine 1.01 g (19.9 mmol) of the Product of Example 48, Step A, 30 mLof DMF, 1.33 g (6.96 mmol) of methyl2,2-difluoro-2-(fluorosulfonyl)acetate and 0.75 g (3.97 g) of CuI. Heatthe mixture at 60°-80° C. for 3 hours, then concentrate to a residue.Dilute the residue with water, extract with CH₂ Cl₂, and concentrate invacuo to a residue. Chromatograph (silica gel, 30% EtOAc/hexane, then10% MeOH/CH₂ Cl₂ +NH₄ OH) to give 0.15 g of the product compound. MassSpec.: MH⁺ =451.1

Step B: ##STR263##

Hydrolyze the product of Step A using essentially the same procedure asdescribed in Preparative Example 1, Step G, to give the productcompound. Mass Spec.: MH⁺ =379

PREPARATIVE EXAMPLE 72 ##STR264## Step A: ##STR265##

Dissolve 20 g (50 mmol) of the Product of Example 1, Step F, in 400 mLof concentrated H₂ SO₄, cool to -5° C. and add 5.1 g (50 mmol) of KNO₃in small portions. Stir for 3 hours, cool the mixture and slowly basifywith 50% NaOH (aqueous). Extract with CH₂ Cl₂ (3×500 mL), dry thecombined extracts over MgSO₄, and concentrate in vacuo to a residue.Chromatograph (silica gel, 50% EtOAc/hexane) to give 16.33 g of theproduct compound (72i) and 2.6 g of the product compound (72ii).

For product compound (72i), Mass Spec.: MH⁺ =428.

For product compound (72ii), Mass Spec.: MH⁺ =428.

Step B: ##STR266##

Hydrolyze 5.46 g (12.76 mmol) of the Product of (72i) from Step A, viasubstantially the same procedure as described for Example 358, Step A,to give 4.34 g of the product compound. Mass Spec.: MH⁺ =356

PREPARATIVE EXAMPLE 73 ##STR267## Step A: ##STR268##

Combine 1.6 g of the Product (54i) of Preparative Example 54, Step B, 12mL of CH₂ Cl₂, and 1.16 g of tetrabutylammonium nitrate, cool to 0° C.and slowly add (dropwise) a solution of 0.8 g of TFAA in 2 mL of CH₂Cl₂. Stir for 6 hours at 0° C., let the mixture stand at 0° C.overnight, then wash successively with saturated NaHCO₃ (aqueous), waterand brine, and dry over Na₂ SO₄. Concentrate in vacuo to a residue, thenchromatograph (silica gel, 30% EtOAc/hexane) to give 0.38 g of theproduct compound.

Step B: ##STR269##

Hydrolyze 0.38 g of the Product of Step A via substantially the sameprocedure as described for Example 358, Step A, to give 0.235 g of theproduct compound.

EXAMPLE 1 1-(4-PYRIDYLACETYL)-4-(8-CHLORO-5,6-DIHYDRO-11H-BENZO5,6!CYCLOHEPTA 1,2-b!PYRIDIN-11-YLIDENE)PIPERIDINE ##STR270##

To a mixture of 528 mg (1.7 mmol) of 4-(8-chloro-5,6-dihydro-11H-benzo5,6!cyclohepta 1,2-b!pyridin-11-ylidene)piperidine (product fromPreparative Example 1, Step G), 274 mg (1.7 mmol) of 4-pyridylaceticacid hydrochloride, and 242 mg (1.8 mmol) of HOBT in 5 mL of dry CH₂ Cl₂at -15° C. and under a nitrogen atmosphere was added dropwise 0.17 mL(1.5 mmol) of Et₃ N followed by a solution of 363 mg (1.9 mmol) of DECin 5 mL of dry CH₂ Cl₂. The reaction mixture was slowly allowed to warmto room temperature. After 4 hours the mixture was poured into water andextracted several times with CH₂ Cl₂. The combined organic portions weredried over MgSO₄, filtered, and concentrated in vacuo to give a productwhich was purified via flash chromatography (3% MeOH saturated withammonia in CH₂ Cl₂) 155 mg of1-(4-pyridylacetyl)-4-(8-chloro-5,6-dihydro-11H-benzo 5,6!cyclohepta1,2-b!pyridin-11-ylidene)piperidine as a solid: mp 152°-155° C.

By essentially the same procedure as set forth in Example 1, but usingthe carboxylic acids set forth in column 1, of Table 2 below, in placeof 4-pyridylacetic acid, one can obtain the compounds listed in column 2of Table 2. The compounds listed in Table 2 refer to compounds ofFormula 500.00: ##STR271## wherein R is the substituent in Column 2.

                                      TABLE 2                                     __________________________________________________________________________    EXAMPLE                                                                             COLUMN 1          COLUMN 2          COMPOUND                            __________________________________________________________________________           ##STR272##                                                                                      ##STR273##       glass                               3                                                                                    ##STR274##                                                                                      ##STR275##       white powder                        4                                                                                    ##STR276##                                                                                      ##STR277##       white solid                         5                                                                                    ##STR278##                                                                                      ##STR279##       white crystals mp 200°                                                 C.                                  6                                                                                    ##STR280##                                                                                      ##STR281##       mp 122-125° C.               7                                                                                    ##STR282##                                                                                      ##STR283##       --                                  8                                                                                    ##STR284##                                                                                      ##STR285##       off white powder                    9                                                                                    ##STR286##                                                                                      ##STR287##       glass                               10                                                                                   ##STR288##                                                                                      ##STR289##       white solid                         11                                                                                   ##STR290##                                                                                      ##STR291##       white solid                         12                                                                                   ##STR292##                                                                                      ##STR293##       glass                               13                                                                                   ##STR294##                                                                                      ##STR295##       white solid                         14                                                                                   ##STR296##                                                                                      ##STR297##       glass                               15                                                                                   ##STR298##                                                                                      ##STR299##       mp 176-178° C.               16                                                                                   ##STR300##                                                                                      ##STR301##       glass                               17                                                                                   ##STR302##                                                                                      ##STR303##       mp 200-204° C.               18                                                                                   ##STR304##                                                                                      ##STR305##       glass                               19                                                                                   ##STR306##                                                                                      ##STR307##       glass                               20                                                                                   ##STR308##                                                                                      ##STR309##       yellow solid                        21                                                                                   ##STR310##                                                                                      ##STR311##       off white solid                     22                                                                                   ##STR312##                                                                                      ##STR313##       white solid mp 228° C.                                                 (dec)                               23                                                                                   ##STR314##                                                                                      ##STR315##       white solid mp 205-207°                                                C.                                  24                                                                                   ##STR316##                                                                                      ##STR317##       white powder                        25                                                                                   ##STR318##                                                                                      ##STR319##       white powder                        26                                                                                   ##STR320##                                                                                      ##STR321##       glass                               27                                                                                   ##STR322##                                                                                      ##STR323##       glass                               28                                                                                   ##STR324##                                                                                      ##STR325##       glass                               29                                                                                   ##STR326##                                                                                      ##STR327##       glass                               30                                                                                   ##STR328##                                                                                      ##STR329##       mp 211-215° C.               31                                                                                   ##STR330##                                                                                      ##STR331##       yellow solid                        32                                                                                   ##STR332##                                                                                      ##STR333##       white solid                         33                                                                                   ##STR334##                                                                                      ##STR335##       white solid                         34                                                                                   ##STR336##                                                                                      ##STR337##       glass                               35                                                                                   ##STR338##                                                                                      ##STR339##       solid mp 190-193° C.         36                                                                                   ##STR340##                                                                                      ##STR341##       solid                               37                                                                                   ##STR342##                                                                                      ##STR343##       glass                               38                                                                                   ##STR344##                                                                                      ##STR345##       white solid                         39                                                                                   ##STR346##                                                                                      ##STR347##       glass                               40                                                                                   ##STR348##                                                                                      ##STR349##       mp 218-220° C.               41                                                                                   ##STR350##                                                                                      ##STR351##       light brown solid mp                                                          = 92.7-93° C. MS M.sup.+                                                = 459                              42                                                                                   ##STR352##                                                                                      ##STR353##       white solid mp                                                                = 114.2-115.8° C. MS                                                   M.sup.+  = 506                      43                                                                                   ##STR354##                                                                                      ##STR355##       white solid mp                                                                = 93.3-94.6° C. MS                                                     M.sup.+  = 506                      44                                                                                   ##STR356##                                                                                      ##STR357##       white solid mp                                                                = 112-114.6° C. MS                                                     M.sup.+  = 428                      45                                                                                   ##STR358##                                                                                      ##STR359##       white solid mp                                                                = 94.3-95.5° C. MS                                                     M.sup.+  = 474                      46                                                                                   ##STR360##                                                                                      ##STR361##       white solid mp                                                                = 126.5-127.5° C. MS                                                   M.sup.+  = 607                      47                                                                                   ##STR362##                                                                                      ##STR363##       white solid mp                                                                = 83.6-85.0° C.              48                                                                                   ##STR364##                                                                                      ##STR365##       white solid mp                                                                = 82.7-83.8° C. MS                                                     M.sup.+  = 456                      49                                                                                   ##STR366##                                                                                      ##STR367##       white solid MS M.sup.+  = 534       49a                                                                                  ##STR368##                                                                                      ##STR369##       white solid mp                                                                = 73.5-73.8° C.              288                                                                                  ##STR370##                                                                                      ##STR371##       white solid MH.sup.+  452                 Preparative Ex. 25                                                      299                                                                                  ##STR372##                                                                                      ##STR373##       off white solid MH.sup.+  459             Preparative Ex. 26                                                      300                                                                                  ##STR374##                                                                                      ##STR375##       white solid MH.sup.+  459                 Preparation Ex. 10                                                      __________________________________________________________________________

EXAMPLE 50 1-(2-THIOPHENEACETYL)-4-(8-CHLORO-5,6-DIHYDRO-11H-BENZO5,6!CYCLOHEPTA 1,2-b!PYRIDIN-11-YLIDENE)PIPERIDINE ##STR376##

To a solution of 1.0 gm (3.22 mmole) of4-(8-chloro-5,6-dihydro-11H-benzo 5,6!cyclohepta1,2-b!pyridin-11-ylidene)piperidine and 0.29 mL of pyridine in 20 mL ofdry CH₂ Cl₂ at 0° C. and under an argon atmosphere was added dropwise0.438 mL (3.55 mmol) of 2-thiopheneacetyl chloride. After 30 minutes themixture was washed with 1.0N aqueous NaOH and then brine. The organicportion was dried over Na₂ SO₄, filtered and converted in vacuo toprovide a residue which was purified via flash chromatography (3% MeOHin CH₂ Cl₂) and treated with activated carbon to provide the titlecompound as a glass.

EXAMPLE 51

By essentially the same procedure as set forth in Example 50, but usingthe acid chlorides set forth in Column 1, in Table 3 below, in place of2-thiopheneacetyl chloride, one can obtain the compounds listed inColumn 2 of Table 3. The compounds listed in Table 3 refer to compoundsof Formula 500.00: ##STR377## wherein R is the substituent in Column 2

                                      TABLE 3                                     __________________________________________________________________________    EXAMPLE                                                                             COLUMN 1     COLUMN 2     COMPOUND                                      __________________________________________________________________________    52                                                                                   ##STR378##                                                                                 ##STR379##  solid                                         53                                                                                   ##STR380##                                                                                 ##STR381##  solid mp 158-160° C.                   54                                                                                   ##STR382##                                                                                 ##STR383##  glass                                         55                                                                                   ##STR384##                                                                                 ##STR385##  white powder                                  56                                                                                   ##STR386##                                                                                 ##STR387##  solid mp 126-128° C.                   57                                                                                   ##STR388##                                                                                 ##STR389##  solid mp 137-139° C.                   58                                                                                   ##STR390##                                                                                 ##STR391##  solid mp 104-106° C.                   59                                                                                   ##STR392##                                                                                 ##STR393##  white solid mp 155-157° C.             __________________________________________________________________________

EXAMPLE 65

By essentially the same procedures as set forth in Example 50 above, orExample 4 of U.S. Pat. No. 5,089,496, but using ##STR394## in place of4-(8-chloro-5,6-dihydro-11H-benzo 5,6!cyclohepta1,2-b!pyridin-11ylidene)piperidine, one can obtain the compound##STR395## as a white solid.

EXAMPLE 75 1-(8-CHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLO-HEPTA1,2-b!PYRIDIN-11-YL-4-(4-PYRIDYLACETYL)-PIPERAZINE ##STR396##

To a mixture of 8.5 g (27.2 m mole) of8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo 5,6!cyclohepta1,2-b!pyridine (Preparative Example 7) in 256 mL of anhydrous DMF atroom temperature and under an argon atmosphere was added 2.98 g (27.2 mmole of 4-methylmorpholine, 7.81 g (27.2 m mole) of DEC, 3.68 g (27.2 mmole) of HOBT, and 3.72 g (27.2 m mole) of 4-pyridylacetic acid. Themixture was stirred at room temperature for 22 hours. The mixture waspoured into 3300 mL of CH₂ Cl₂ and washed with 500 mL of water. Theaqueous layer was extracted with 500 mL of CH₂ Cl₂. The combined organicportions were dried over MgSO₄, filtered, and concentrated in vacuo. Theresidue was purified by silica gel column chromatography using asolution of 1.5% (10% NH₄ OH in MeOH) in CH₂ Cl₂. The product wasobtained as a white amorphous solid, M.S. (Mass Spec) M+=433.

By essentially the same procedures as set forth in Example 75 above butusing the compounds set forth in Column 1, Table 4 below, in place of4-pyridylacetic acid, one can obtain compounds of the formula ##STR397##wherein R is as listed in Column 2 of Table 4.

                                      TABLE 4                                     __________________________________________________________________________    EX.                                                                              COLUMN 1       COLUMN 2       CMPD                                         __________________________________________________________________________    76                                                                                ##STR398##                                                                                   ##STR399##    white amorphous solid Mass Spec M.sup.+                                       = 501                                        77                                                                                ##STR400##                                                                                   ##STR401##    white amorphous solid Mass Spec M.sup.+                                       = 512                                        78                                                                                ##STR402##                                                                                   ##STR403##    white amorphous solid Mass Spec M.sup.+                                       = 433                                        79                                                                                ##STR404##                                                                                   ##STR405##    white amorphous solid Mass Spec M.sup.+                                       = 508                                        80                                                                                ##STR406##                                                                                   ##STR407##    white amorphous solid Mass Spec M.sup.+                                       = 432                                        81                                                                                ##STR408##                                                                                   ##STR409##    white amorphous solid Mass Spec M.sup.+                                       = 459                                        __________________________________________________________________________

EXAMPLE 82 8-CHLORO-11-1-(2-(4-PYRIDYL)ACETYL)-4-PIPERIDYL!-6,11-DIHYDRO-5H-BENZO5,6!CYCLOHEPTA 1,2-b!PYRIDINE ##STR410##

Dissolve 0.1 g (0.32 m mole) of8-chloro-11-4-piperidyl!-6,11-dihydro-5H-benzo 5,6!cyclohepta1,2-b!-pyridine (from Example 233), 0.06 g (0.32 m mole) of4-pyridylacetic acid, 0.092 g (0.48 m mole) of DEC, 0.065 g (0.48 mmole) of HOBT and 0.048 g (0.50 m mole) of N-methyl morpholine in 5 mLof DMF and stir at room temperature for 18 hours under nitrogen.Concentrate under vacuo and partition between 100 mL each of EtOAc andwater. Dry the organic layer over sodium sulfate and concentrate undervacuo. The resulting residue is chromatographed on silica gel using 98%dichloro methane and 2% MeOH, saturated with ammonia as the solvent,giving the product as a white waxy solid, mass spec M+=431.

EXAMPLE 82A 8-CHLORO-11-1-(2-(PYRIDYL)ACETYL)-4-PIPERIDYL!-6,11-DIHYDRO-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDINE ##STR411##

By essentially the same procedure as set forth in Example 82, but using3-pyridylacetic acid instead of 4-pyridylacetic acid, the title compoundis obtained as a white solid (M+=431, mp=81.7°-82° C.).

EXAMPLE 83 8-CHLORO-11-1-(2-METHYLSULFONYLOXY-1-PHENYLETHYLCARBONYL)-4-PIPERIDYLIDENE!-6,11-DIHYDRO-5H-BENZO5,6!CYCLOHEPTA 1,2-b!-PYRIDINE ##STR412##

Dissolve 0.40 g (0.9 m mole) of 8-chloro-11-1-(2-hydroxy-1-phenylethylcarbonyl)-4-piperidylidene!-6,11-dihydro-5H-benzo5,6!cyclohepta- 1,2-b!pyridine (Example 41 of Table 2) in 10 mL ofpyridine and stir under nitrogen. Add 0.15 g (1.3 m mole) ofmethanesulfonyl chloride and stir for 20 hours. Concentrate under vacuoand triturate the residue with ether. Purify the resulting solid bysilica gel chromatography using 2% MeOH saturated with ammonia, and 98%CH₂ Cl₂ as the solvent. The product is obtained as a white solid,mp=110.7°-111.6° C.

EXAMPLE 84 8-CHLORO-11-1-(2-ACETYLMERCAPTO-1-PHENYLETHYLCARBONYL)-4-PIPERIDYLIDENE!-6,11-DIHYDRO-5H-BENZO5,6!CYCLOHEPTA 1,2-b!-PYRIDINE ##STR413##

Dissolve 0.3 g (0.56 m mole) of 8-chloro-11-1-(2-methanesulfonyloxy-1-phenylethylcarbonyl)-4-piperidylidene!-6,11-dihydro-5H-benzo5,6!cyclohepta- 1,2-b!pyridine (Formula 5.6 of Example 83) in 5 mL ofDMF and add 0.2 g (0.6 m mole) of cesium thioacetate (preparationdescribed in Synthetic Communications, 13, 553, 1983). Stir the reactionat 80° C. for twenty hours then concentrate under vacuo. Purify theresidue by silica gel chromatography using 70% EtOAc and 30% hexane asthe solvent. The product is obtained as a light brown solid,mp=92.7°-93° C.

EXAMPLE 85 8-CHLORO-11-1-(1-(2,3-DIHYDRO-3-OXO-1,2-BENZOISOTHIAZOL-S,S-DIOXIDE-2-YL)METHYLCARBONYL)-4-PIPERIDYLIDENE!-6,11-DIHYDRO-5H-BENZO5,6!CYCLOHEPTA 1,2-b!-PYRIDINE ##STR414##

Dissolve 0.46 g (1.7 m mole) of 8-chloro-11-1-(2-hydroxyethylcarbonyl)-4-piperidylidene!-6,11-dihydro-5H-benzo5,6!cyclohepta 1,2,b!pyridine (Example 49a of Table 2) in 30 mL of DMFand stir at 0° C. under nitrogen. Add 0.55 g (2.1 m mole) of triphenylphosphine and 0.36 g (2.1 m mole) of diethyl azodicarboxylate. Stirreaction mixture at 70° C. for 3 days, then concentrate under vacuo. Theresidue was dissolved in mL of 1N HCl and washed with 100 mL of EtOAc.The water layer was neutralized with 1N NaOH and the mixture wasextracted with EtOAc. The organic layer was dried over MgSO₄ andconcentrated under vacuo. The residue was purified by silica gelchromatography using 90% EtOAc and 10% hexane as the solvent, giving theproduct as a white solid, mass spec. M+=534.

EXAMPLE 86 8-CHLORO-11-1-(1-(3-PYRIDYL)METHYLTHIOCARBONYL)-4-PIPERIDYLIDENE!-6,11-DIHYDRO-5H-BENZO5,6!CYCLOHEPTA 1,2-b!PYRIDINE ##STR415##

Dissolve 0.50 g (0.12 m mole) of 8-chloro-11-1-(1-(3-pyridyl)methylcarbonyl)-4-piperidylidene!-6,11-dihydro-5H-benzo5,6!cyclohepta 1,2-b!-pyridine (Example 2 of Table 2) and 0.5 g (0.12 mmole) of2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide(Lawesson's Reagent) in 15 mL of toluene and stirr for 18 hours at roomtemperature and 18 hours at 80° C., under nitrogen. Filter the reactionmixture and concentrate under vacuo. Dissolve the residue in 50 mL of 1NHCl and extract with 200 mL of CH₂ Cl₂. The water layer was neutralizedwith Na₂ CO₃ and extracted with CH₂ Cl₂. The organic layer was driedover MgSO₄ and concentrated under vacuo giving the product as a whitesolid, mp=92°-93° C.

EXAMPLE 87 10,11-DIHYDRO-5-1-(1-(4-PYRIDYL)METHYLCARBONYL)-4-PIPERIDYLIDENE!-5H-DIBENZOa,d!CYCLOHEPTENE ##STR416##

Dissolve 0.15 g (0.6 m mole) of10,11-dihydro-5-(4-piperidylidene)-5H-dibenzo a,d!cycloheptene, 0.096 g(0.55 m mole) of 4-pyridylacetic acid hydrochloride, 0.16 g (0.83 mmole) of DEC and 0.075 g (0.55 m mole) of HOBT in 5 mL of DMF and stirat room temperature for 18 hours under nitrogen. Concentrate under vacuoand partition between 100 mL each of EtOAc and 10% aqueous sodiumhydrogenphosphate. Dry the organic layer over MgSO₄ and concentrateunder vacuo. The resulting residue is chromatographed on silica gelusing 98% dichloro methane and 2% MeOH, saturated with ammonia as thesolvent, giving the product as a white waxy solid, mp=162.8°-163.4° C.

EXAMPLE 180 1-1-(4-PYRIDINYLACETYL)-4-3,8-DICHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!PIPERIDINE ##STR417##

Dissolve 0.18 g (0.51 mmole) of 3,8-dichloro11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo 5,6!cycohepta1,2-b!pyridine, 0.088 g (0.51 mmole ) 4-pyridylacetic acid, 0.117 g(0.61 mmole) of DEC, 0.082 g (0.61 mmole) HOBT and 0.071 g (0.71 mmole)N-methyl morpholine in 5 mL of DMF and stir for 18 hours under nitrogen.Concentrate under vacuo and partion between EtOAc and water. Dry organiclayer over sodium sulfate and concentrate in vacuo. The resultingresidue is chromatogaphed on silica gel using 95% CH₂ Cl₂ and 5% MeOH,saturated with ammonia as the solvent. The product is obtained as whitesolid, mp=113°-114° C.

EXAMPLE 181 ##STR418##

By essentially the same procedure as set forth in Example 180, but using8-bromo-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo5,6!cyclohepta 1,2-b!pyridine instead of3,8-dichloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo5,6!-cyclohepta 1,2-b!pyridine, compound 5.48 was obtained as anoff-white solid, mp=94.3°-94.7° C.

EXAMPLE 182 ##STR419##

To a stirred solution of phenyl isocyanate (1.27 mmole) in 15 ml ofanhydrous CH₂ Cl₂ at room temperature and under an argon atmosphere wasadded dropwise over 20 minutes, a solution of8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo 5,6!cyclohepta1,2-b!pyridine (1.27 mmole) in 5 ml of anhydrous CH₂ Cl₂. The mixturewas stirred at room temperature for 20 hours. The mixture was pouredinto 700 ml of CH₂ Cl₂ and washed with 100 ml of saturated NaHCO₃. Theorganic portion was dried over MgSO₄, filtered, and concentrated invacuo. The residue was purified by silica gel chromatography using asolution of 1.0% (10% NH₄ OH in MeOH) in CH₂ Cl₂. The product wasobtained as a white amorphous solid, M.S. (Mass Spec) M+=433.

EXAMPLE 183 ##STR420##

To a 5.0 ml reaction vial was added8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo 5,6!cyclohepta1,2-b!pyridine (1.0 mmole) and N-ethoxycarbonyl-4-aminopyridine (0.99mmole). The vial was capped and placed in an oil bath at 170° C. andstirred for 5 hours. The residue was purified by silica gelchromatography using a solution of 3.0% (10% NH₄ OH in MeOH) in CH₂ Cl₂.The product was obtained as a white amorphous solid, M.S. (Mass Spec)M+=434.

EXAMPLE 184 1-(8-CHLORO-6,11-DIHYDRO-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YL)-4-(3-PYRIDINYLACETYL)piperazine 1-N-OXIDE##STR421##

The title compound from Preparative Example 11D (0.5 grams) (1.5 mmoles)was reacted with 3-pyridylacetic acid (0.208 grams) (1.5 mmoles) underthe conditions described in Example 75 to give the title compound(Yield: 0.439 grams, 95%, MH⁺ 449).

EXAMPLE 185 1-(8-CHLORO-6,11-DIHYDRO-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YL)-4-(3-PYRIDINYLACETYL 1-N-OXIDE)PIPERAZINE 1-N-OXIDE##STR422##

The title compound from Preparative Example 11D (0.5 grams) (1.5 mmoles)was reacted with the title compound from Preparative Example 8 (0.232grams) (1.5 mmoles) under the conditions described in Example 75 to givethe title compound (Yield: 0.6454 grams, 92%, MH⁺ 465.2).

EXAMPLE 186 N-BENZYL 4-(8-CHLORO-6,11-DIHYDRO-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YL)-1-PIPERAZINECARBOXAMIDE ##STR423##

The title compound from Example 75 was reacted with benzyl isocyanateunder the conditions described in Example 182 above to give the titlecompound (Yield: 79%, MH⁺ 447).

EXAMPLE 187

By essentially the same procedure as Example 183, with the exceptionthat 3-ethoxycarbonylaminopyridine or 2-ethoxycarbonylaminopyridine(Preparative Example 12) is used instead of using4-ethoxycarbonylaminopyridine, the compound ##STR424## was obtained,respectively.

EXAMPLE 188 4-(8-CHLORO-6,11-DIHYDRO-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YL)-N-METHYL-N-(3-PYRIDINYL)-1-PIPERAZINECARBOXAMIDE##STR425##

Compound 6.7 from Example 187 (10 grams) (23.1 mmoles) in DMSO (37.6ml.) was added to a solution of powdered KOH (2.62 grams) (23.1 mmoles)in DMSO (25 ml.) and the mixture was stirred at 25° C. for 3 minutes.Iodomethane (1.4518 ml.) (23.1 mmoles) was added and the mixture wasstirred at 25° C. for 15 minutes. The mixture was poured into water andextracted with CH₂ Cl₂. The latter was dried (magnesium sulphate),filtered and evaporated to dryness. The product was purified bychromatography on silica gel using 3-5% (10% concentrated ammoniumhydroxide in MeOH)--CH₂ Cl₂ as the eluant to give the title compound(Yield: 6.28 grams, 61%, MH⁺ 448).

EXAMPLES 189-218

By essentially the same procedures as set forth in Example 75 above butusing the compounds set forth in Column 1, Table 5 below, in place of4-pyridylacetic acid, one can obtain compounds of the formula ##STR426##wherein R is as listed in Column 2 of Table 5.

                                      TABLE 5                                     __________________________________________________________________________    EX.                                                                              COLUMN 1             COLUMN 2             CMPD                             __________________________________________________________________________    189                                                                               ##STR427##                                                                                         ##STR428##          white amorphous solid                                                         MH.sup.+  475                    190                                                                               ##STR429##                                                                                         ##STR430##          white amorphous solid                                                         MH.sup.+  460                    191                                                                               ##STR431##                                                                                         ##STR432##          white amorphous solid                                                         MH.sup.+  447                    192                                                                               ##STR433##                                                                                         ##STR434##          white amorphous solid                                                         MH.sup.+  467                    193                                                                               ##STR435##                                                                                         ##STR436##          white amorphous solid                                                         MH.sup.+  539                    194                                                                               ##STR437##                                                                                         ##STR438##          white amorphous solid                                                         MH.sup.+  467                    195                                                                               ##STR439##                                                                                         ##STR440##          white amorphous solid                                                         MH.sup.+  439                    196                                                                               ##STR441##                                                                                         ##STR442##          white amorphous solid                                                         MH.sup.+  433                    197                                                                               ##STR443##                                                                                         ##STR444##          white amorphous solid                                                         MH.sup.+  449                    198                                                                               ##STR445##                                                                                         ##STR446##          white amorphous solid                                                         MH.sup.+  461                    199                                                                               ##STR447##                                                                                         ##STR448##          white amorphous solid                                                         MH.sup.+  467                                            5.72A = Isomer A                                                              5.72B = Isomer B                                      200                                                                               ##STR449##                                                                                         ##STR450##          white amorphous solid                                                         MH.sup.+  467                    201                                                                               ##STR451##                                                                                         ##STR452##          white amorphous solid                                                         MH.sup.+  453                    202                                                                               ##STR453##                                                                                         ##STR454##          white amorphous solid                                                         MH.sup.+  525                    203                                                                               ##STR455##                                                                                         ##STR456##          white amorphous solid                                                         MH.sup.+  525                    204                                                                               ##STR457##                                                                                         ##STR458##          white amorphous solid                                                         MH.sup.+  497                    205                                                                               ##STR459##                                                                                         ##STR460##          white amorphous solid                                                         MH.sup.+  481                    206                                                                               ##STR461##                                                                                         ##STR462##          white amorphous solid                                                         MH.sup.+  453                    207                                                                               ##STR463##                                                                                         ##STR464##          white amorphous solid                                                         MH.sup.+  505                    208                                                                               ##STR465##                                                                                         ##STR466##          white amorphous solid                                                         MH.sup.+  471                    209                                                                               ##STR467##                                                                                         ##STR468##          white amorphous solid                                                         MH.sup.+  489                    210                                                                               ##STR469##                                                                                         ##STR470##          white amorphous solid                                                         MH.sup.+  505                    211                                                                               ##STR471##                                                                                         ##STR472##          white amorphous solid                                                         MH.sup.+  505                    212                                                                               ##STR473##                                                                                         ##STR474##          white amorphous solid                                                         MH.sup.+  505                    213                                                                               ##STR475##                                                                                         ##STR476##          white amorphous solid                                                         MH.sup.+  595                    214                                                                               ##STR477##                                                                                         ##STR478##          white amorphous solid                                                         MH.sup.+  561                    215                                                                               ##STR479##                                                                                         ##STR480##          white amorphous solid                                                         MH.sup.+  461                    216                                                                               ##STR481##                                                                                         ##STR482##          white amorphous solid                                                         MH.sup.+  591                    217                                                                               ##STR483##                                                                                         ##STR484##          white amorphous solid                                                         MH.sup.+  503                    218                                                                               ##STR485##                                                                                         ##STR486##          white amorphous solid                                                         MH.sup.+  519                    __________________________________________________________________________

EXAMPLES 219-222

By essentially the same procedure as set forth in Example 1, but usingthe acids set forth in Column 1 of Table 6 below in place of4-pyridylacetic acid, the compounds listed in Column 2 of Table 6 areobtained. The compounds listed in Table 6 refer to compounds of Formula500.00: ##STR487## wherein R is the substituent in Column 2.

                                      TABLE 6                                     __________________________________________________________________________    EX.                                                                              COLUMN 1      COLUMN 2       CMPD                                          __________________________________________________________________________    219                                                                               ##STR488##                                                                                  ##STR489##    white amorphous solid MH.sup.+  482 m.p.                                      = 192-193° C.                          220                                                                               ##STR490##                                                                                  ##STR491##    white amorphous solid MH.sup.+  502 m.p.                                      = 282-285° C.                          221                                                                               ##STR492##                                                                                  ##STR493##    white amorphous solid MH.sup.+  485           222                                                                               ##STR494##                                                                                  ##STR495##    white amorphous solid MH.sup.+  514           __________________________________________________________________________

EXAMPLE 223 A. (+)-1-(8-CHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11(R)-YL)-4-(3-PYRIDINYLACETYL)PIPERAZINE ##STR496##

The title R(+) diastereoisomer from Preparative Example 19 was reactedwith 3-pyridylacetic acid under the same conditions as described inExample 75 to give the title compound (Yield: 88%, MH⁺ 433).

B. (-)-1-(8-CHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA2-b!PYRIDIN-11(S)-YL)-4-(3-PYRIDINYLACETYL)PIPERAZINE ##STR497##

The title S(-) diastereoisomer from Preparative Example 19 above wasreacted with 3-pyridylacetic acid under the same conditions as describedin Example 75 to give the title compound (Yield: 96%, MH⁺ 433).

EXAMPLE 224 A. (+)-4-(8-CHLORO-6,11-DIHYDRO-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11(R)-YL)-N-(3-PYRIDINYL)-1-PIPERAZINECARBOXYLATE##STR498##

The title R(+) diastereoisomer from Preparative Example 19 was reactedwith 3-ethoxycarbonylaminopyridine under the same conditions asdescribed in Example 75 to give the title compound (Yield: 81%, MH⁺434).

B. (-)-4-(8-CHLORO-6,11-DIHYDRO-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11(S)-YL)-N-(3-PYRIDINYL)-1-PIPERAZINECARBOXAMIDE##STR499##

The title S(-) diastereoisomer from Preparative Example 19 was reactedwith 3-ethoxycarbonylaminopyridine under the same conditions asdescribed in Example 75 to give the title compound (Yield: 80%, MH⁺434).

EXAMPLE 225 A. (+)-1-(8-CHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11(R)-YL)-4- (1-ACETYL-4-PIPERIDINYL)ACETYL!PIPERAZINE##STR500##

The title R(+) diastereoisomer from Preparative Example 19 above wasreacted with 1-N-acetylpiperidinyl-3-acetic acid under the sameconditions as described in Example 75 to give the title compound (Yield:52% MH⁺ 481).

B. (+1-(8-CHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11(S)-YL)-4- (1-ACETYL-4-PIPERIDINYL)ACETYL!PIPERAZINE##STR501##

The title S(-) diastereoisomer from Preparative Example 19 above wasreacted with 1-N-acetylpiperidinyl-3-acetic acid under the sameconditions as described in Example 75 to give the title compound (Yield:53% MH⁺ 481).

EXAMPLE 226 A. (+)-1-(8-CHLORO-6,11-DIHYDRO-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11(R)-YL)-4- (1-ACETYL-4-PIPERIDINYL)CARBONYL!PIPERAZINE##STR502##

The title R(+) diastereoisomer from Preparative Example 19 was reactedwith 1-N-acetylisonipecotic acid under the same conditions as describedin Example 75 to give the title compound (Yield: 90%, MH⁺ 467).

B. (-)-1-(8-CHLORO-6,11-DIHYDRO-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11(S)-YL)-4- (1-ACETYL-4-PIPERIDINYL)CARBONYL!PIPERAZINE##STR503##

The title S(-) diastereoisomer from Preparative Example 19 was reactedwith 1-N-acetylisonipecotic acid under the same conditions as describedin Example 75 to give the title compound (Yield: 93%, MH⁺ 467).

EXAMPLE 227 4-(8-CHLORO-5,6-DIHYDRO-11H-BENZO- 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE)-1- (4-PYRIDINYL)ACETYL!-PIPERIDINE N1OXIDE##STR504##

To a mixture of 0.933g (3 mmol) of 4-(8-chloro-5,6-dihydro-11H-benzo-5,6!cyclohepta(1,2-b!pyridin-11-ylidene)-piperidine (product fromPreparative Example 1, step G), 0.46g (3 mmol) of 4-pyridyl acetic acidN-oxide (prepared as described in Preparative Example 8)1-hydroxybenzotriazole (0.40 g, 3 mmol) in 20 mL of DMF at ˜4° C. andunder nitrogen atmosphere was added N-methyl morpholine (1.65 mL, 15mmol) followed by DEC an reaction stirred overnight at room temperature.The volatiles were stripped off and the resulting semi-solid waspartitioned between water and EtOAc. The aqueous phase was washed twicewith EtOAc. Combined EtOAc fractions were dried over Na₂ SO₄ andconcentrated. The crude product was purified via flash chromatography onsilica gel (first eluting with 3% and then 5% MeOH saturated withammonia in CH₂ Cl₂) to give the title compound as a light brown solid(0.2 g mp=128°-130° C. MH⁺ 446).

EXAMPLE 228 4-(8-CHLORO-5,6-DIHYDRO-11H-BENZO- 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE)-1- (3-PYRIDINYL)ACETYL!-PIPERIDINE N1OXIDE##STR505##

By essentially the same procedure as set forth in Example 227, but using3-pyridyl acetic acid N-oxide (Preparative Example 9) instead of4-pyridyl acetic acid N-oxide the title compound was obtained as a whitesolid (mp=120°-121° C., MH⁺ =466).

EXAMPLE 229 4-(8-CHLORO-5,6-DIHYDRO-11H-BENZO- -5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE)-1- (-3-PYRIDINYL)ACETYL!-PIPERIDINE N4 OXIDE##STR506##

4-(8-chloro-5,6-dihydro-11H-benzo- 5,6!cyclohepta1,2-b!pyridin-11-ylidene)-1- (3-pyridinyl)acetyl!-piperidine (1.0 g,2.33 mmol) was dissolved in dry CH₂ Cl₂ (50 mL) at -10° C. MCPBA (80-85%purity 1.1 g, 5.13 mmol) was added and the reaction stirred at thattemperature for 95 minutes. The reaction mixture was washed with sodiumbisulfite and then with 10% NaOH. The organic phase was dried over MgSO₄and then concentrated. Purification on silica gel eluting, first with4%, 6% and then 10% MeOH in CH₂ Cl₂ gave rise to the title compound as awhite solid (0.2 g, 0.77 mmol MH⁺ =446).

EXAMPLE 230 4-(8-CHLORO-5,6-DIHYDRO-11H-BENZO- 5,69 CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE)-1- (4-PYRIDINYL)ACETYL!-PIPERIDINE N4 OXIDE##STR507##

By essentially the same procedures as set forth in Example 229 above,but using 4-(8-chloro-5,6-dihydro-11H-benzo- 5,6!cyclohepta1,2-b!pyridin-11-ylidene)-1- (4-pyridinyl)acetyl!-piperidine instead of4-(8-chloro-5,6-dihydro-11H-benzo- 5,6!cyclohepta1,2-b!pyridin-11-ylidene)-1- (3-pyridinyl)acetyl!-piperidine the titlecompound was obtained as an off-white solid (MH⁺ =446).

EXAMPLE 231 A.8-CHLORO-11-(1-ETHOXYCARBONYL-4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO5,6!CYCLOHEPTA 1,2-b!PYRIDINE N-OXIDE ##STR508##

8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo5,6!cyclohepta 1,2-b!pyridine (5 g, 13.06 mmol) was dissolved in CH₂ Cl₂at -10° C. 3-Chlorobenzoic acid (4.9 g, 15.67 mmol) was then added andthe reaction mixture stirred for 95 minutes. The reaction mixture wastaken up in CH₂ Cl₂ and extracted with sodium bisulfite, 10% NaOH. Thecrude reaction product was purified on silica gel eluting first with 1%and then with 2% MeOH in CH₂ Cl₂ to give the title compound (2.7 g, MH⁺399).

B. 8-CHLORO-11-(4-PIPERIDYLIDENE)-6,11-DIHYDRO-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIRIDINE N-OXIDE ##STR509##

By essentially the same procedures as set forth in Preparative Example 1step G, but using8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo5,6!cyclohepta 1,2-b!pyridine N-oxide instead of8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo5,6!cyclohepta 1,2-b!pyridine, the title compound was obtained and usedfor the next reaction without further purification (MH+ 327),

C. 4-(8-CHLORO-5,6-DIHYDRO-11H-BENZO5,6!CYCLOHEPTA(1,2-b!PYRIDIN-11-YLIDENE)-1-(3-PYRIDINYL)ACETYL!PIPERIDINE N1,N4 DIOXIDE ##STR510##

By essentially the same procedure as set forth in Example 227, but using3-pyridyl acetic acid N-oxide (Preparative Example 9) instead of4-pyridyl acetic acid N-oxide and8-chloro-11-(4-piperidylidene)-6,11-dihydro-5H-benzo 5,6!cyclohepta1,2-b!pyridine N-oxide instead of8-chloro-11-(4-piperidylidene)-6,11-dihydro-5H-benzo 5,6!cyclohepta1,2-b!pyridine, the title compound was obtained as a white solid(mp=105°-107° C., MH⁺ =462).

EXAMPLE 232 4-(8-CHLORO-5,6-DIHYDRO-11H-BENZO- 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE)-1- (4-PYRIDINYL)ACETYL!-PIPERIDINE N1,N4DIOXIDE ##STR511##

By essentially the same procedure as set forth in Example 227, but using8-chloro-11-(4-piperidylidene)-6,11-dihydro-5H-benzo 5,6!cyclohepta1,2-b!pyridine N-oxide instead of8-chloro-11-(4-piperidylidene)-6,11-dihydro-5H-benzo 5,6!cyclohepta1,2-b!pyridine, the title compound was obtained as a light brown solid(MH⁺ =462).

EXAMPLE 233 A. 8-CHLORO-6,11-DIHYDRO-11-(4-PIPERIDINYL)-5H-BENZO5,6!CYCLOHEPTA 1,2!PYRIDINE (Product A) and6,11-DIHYDRO-11-(4-PIPERIDINYL)-5H-BENZO 5,6!-CYCLOHEPTA 1,2-b!PYRIDINE(Product B) ##STR512##

To a solution 66.27 g (0.21 mole) of 4-(8-chloro-5,6-dihydro-11H-benzo5,6!cyclohepta(1,2-b!pyridin-11-ylidene)-piperidine (product fromPreparative Example 1 Example, step G), in THF (1 L) was added lithiumaluminum hydride (24.32 g, 0.64 mole) and the reaction mixture washeated to reflux overnight. The reaction mixture was then cooled to roomtemperature and ˜3 L of diethyl ether is added followed by dropwiseaddition of saturated sodium sulfate until a white gray precipitateforms. MgSO₄ was then added to the separated organic layer and stirredfor 30 minutes. All the volatiles were then removed and the resultingcrude mixture was chromatographed on a silica gel column eluting with10% MeOH saturated with ammonia in CH₂ Cl₂. The material obtainedcontained both the desired compound and the des-chloro compound.Separation on HPLC using reverse phase column and eluting with 40%MeOH-water afforded the desired compounds as white solids (Product A'smp=95.2°-96.1° C., Product B's mp=145.1°-145.7° C.).

B. 4-(8-CHLORO-6,11-DIHYDRO-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YL)-1- (3-PYRIDINYL)ACETYL!-PIPERIDINE N1 OXIDE##STR513##

By essentially the same procedure as set forth in Example 227, but using3-pyridyl acetic acid N-oxide (Preparative Example 9) instead of4-pyridyl acetic acid N-oxide and8-chloro-6,11-dihydro-11-(4-piperidinyl)-5H-benzo 5,6!cyclohepta1,2-b!pyridine (product from Example 233A ) instead of4-(8-chloro-5,6-dihydro-11H-benzo-5,6!cyclohepta(1,2-b!pyridin-11-ylidene)-piperidine, the title compoundwas obtained as a white solid (mp=117°-118° C., MH⁺ =414).

EXAMPLE 234 4-(8-CHLORO-6,11-DIHYDRO-5H-BENZO5,6!CYCLOHEPTA(1,2-b!PYRIDIN-11-YL)-1- (4-PYRIDINYL)ACETYL!-PIPERIDINEN1 OXIDE ##STR514##

By essentially the same procedure as set forth in Example 227, but using8-chloro-6,11-dihydro-11-(4-piperidinyl)-5H-benzo 5,6!cyclohepta1,2-b!pyridine (product from Example 233A) instead of4-(8-chloro-5,6-dihydro-11H-benzo-5,6!cyclohepta(1,2-b!pyridin-11-ylidene)-piperidine (product fromPreparative Example 1, step G), the title compound was obtained as awhite solid (mp=125°-126° C., MH⁺ =414).

EXAMPLE 235 A. ETHYL 4-(8-CHLORO-6,11-DIHYDRO-5H-BENZO5,6!CYCLOHEPTA(1,2-b!PYRIDIN-11-YL)-1-PIPERIDINECARBOXYLATE ##STR515##

8-Chloro-6,11-dihydro-11-(4-piperidinyl)-5H-benzo 5,6!cyclohepta1,2-b!pyridine (product from Example 233A) (4.18 g, 13 mmol) wasdissolved in toluene (175 mL). Ethyl chloroformate (11.6 g, 110 mmol,10.2 mL) was then added and the reaction mixture was heated to ˜120° C.overnight. All volatiles were stripped off and the crude product waspurified on silica gel column eluting with 50% EtOAc-hexanes to give thetitle compound as a white solid (MH⁺ 385).

B. ETHYL 4-(8-CHLORO-6,11-DIHYDRO-5H-BENZO5,6!CYCLOHEPTA(1,2-b!PYRIDIN-11-YL)-1-PIPERIDINECARBOXYLATE N OXIDE##STR516##

By essentially the same procedure as set forth in Example 231, but usingethyl 4-(8-chloro-6,11-dihydro-5H-benzo-5,6!cyclohepta(1,2-b!pyridin-11-yl)-1-piperidinecarboxylate (productfrom Example 235A) instead of8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo5,6!cyclohepta 1,2-b!pyridine, the title compound was obtained as awhite solid (mp=81.7°-82.5° C., MH⁺ =400).

C. 4-(8-CHLORO-6,11-DIHYDRO-5H-BENZO5,6!CYCLOHEPTA(1,2-b!PYRIDIN-11-YL)-1-PIPERIDINE N OXIDE ##STR517##

By essentially the same procedure as set forth in Preparative Example 1step G, but using ethyl 4-(8-chloro-6,11-dihydro-5H-benzo-5,6!cyclohepta 1,2-b!pyridin-11-yl)-1-piperidinecarboxylate N1 oxide(product from Example 235B) instead of8-chloro-11-(1-ethoxycarbonyl-4-piperidylidene)-6,11-dihydro-5H-benzo5,6!cyclohepta 1,2-b!pyridine, the title compound was obtained as asolid (MH⁺ =329).

D. 4-(8-CHLORO-6,11-DIHYDRO-5H-BENZO5,6!CYCLOHEPTA(1,2-b!PYRIDIN-11-YL)-1- (3-PYRIDINYL)ACETYL!-PIPIERIDINEN4 OXIDE ##STR518##

By essentially the same procedure as set forth in Example 227, but using3-pyridyl acetic acid instead of 4-pyridyl acetic acid N-oxide and4-(8-chloro-6,11-dihydro-5H-benzo- 5,6!cyclohepta1,2-b!pyridin-11-yl)-1-piperidine N oxide (product from Example 235C)instead of 4-(8-chloro-5,6-dihydro-11H-benzo- 5,6!cyclohepta1,2-b!pyridin-11-ylidene)piperidine, the title compound was obtained asa white solid (mp=61.8°-62.3° C., MH⁺ =448).

EXAMPLE 236 4-(8-CHLORO-6,11-DIHYDRO-5H-BENZO-5,6!CYCLOHEPTA(1,2-b!PYRIDIN-11-YL)-1- (4-PYRIDINYL)ACETYL!-PIPERIDINEN4 OXIDE ##STR519##

By essentially the same procedure as set forth in Example 227, but using4-pyridyl acetic acid instead of 4-pyridyl acetic acid N-oxide and4-(8-chloro-6,11-dihydro-5H-benzo-5,6!cyclohepta(1,2-b!pyridin-11-yl)-1-piperidine N oxide (product fromExample 235C) instead of 4-(8-chloro-5,6-dihydro-11H-benzo-5,6!cyclohepta 1,2-b!pyridin-11-ylidene)piperidine, the title compoundwas obtained as a white solid (mp=116.7°-117.6° C., MH⁺ =448).

EXAMPLE 237 4-(8-CHLORO-6,11-DIHYDRO-5H-BENZO-5,6!CYCLOHEPTA(1,2-b!PYRIDIN-11-YL)-1- (3-PYRIDINYL)ACETYL!-PIPERIDINEN1, N4 OXIDE ##STR520##

4-(8-Chloro-6,11-dihydro-5H-benzo-5,6!cyclohepta(1,2-b!pyridin-11-yl)-1- (3-pyridinyl)acetyl!-piperidine,from Example 82A, (0.5 g, 1.2 mmol) was dissolved in CH₂ Cl₂ at about-18° C. MCPBA (0.62 g, 3.6 mmol) was added and the reaction stirred for1.5 hours. The reaction mixture was extracted with 10% sodium bisulfite,10% NaOH and then dried with MgSO₄, filtered and concentrated. The crudeproduct was purified on silica gel eluting with 7% MeOH saturated withammonia in CH₂ Cl₂ to give the title compound as a white solid (0.51 g,91% yield MH⁺ 464).

EXAMPLE 238 4-(8-CHLORO-6,11-DIHYDRO-5H-BENZO-5,6!CYCLOHEPTA(1,2-b!PYRIDIN-11-YL)-1- (4-PYRIDINYL)ACETYL!-PIPERIDINEN1, N4 OXIDE ##STR521##

By essentially the same procedure as set forth in Example 237, but using4-(8-chloro-6,11-dihydro-5H-benzo- 5,6!cyclohepta1,2-b!pyridin-11-yl)-1-(4-pyridinyl)acetyl!-piperidine (product fromExample 82) instead of 4-(8-chloro-6,11-dihydro-5H-benzo- 5,6!cyclohepta1,2-b!pyridin-11-yl)-1-(3-pyridinyl)acetyl!-piperidine, the titlecompound was obtained as a white solid (mp=85°-85.6° C., MH⁺ =464).

EXAMPLE 239 4-(8-CHLORO-3-METHOXY-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE)-1- (3-PYRIDINYL!ACETYL!-PIPERIDINE ##STR522##

By essentially the same procedure as set forth in Example 180, but using8-chloro-3-methoxy-11-(4-piperidylidene)-6,11-dihydro-5H-benzo5,6!-cyclohepta 1,2-b!pyridine (Preparative Example 20) instead of3,8-dichloro-11-(1-acetyl-4-piperidylidene)-6,11-dihydro-5H-benzo5,6!cyclohepta 1,2-b!pyridine the title compound was obtained as a whitesolid (MH⁺ 460).

EXAMPLE 240 4-(8-CHLORO-3-HYDROXY-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE)-1- (3-PYRIDINYL!-ACETYL!-PIPERIDINE ##STR523##

4-(8-Chloro-3-methoxy-5,6-dihydro-11H-benzo 5,6!cyclohepta1,2-b!pyridin-11-ylidene)-1- (3-pyridinyl!acetyl!-piperidine (0.24 g,0.54 mmol) (Example 239) was dissolved in CH₂ Cl₂ at 0° C. undernitrogen atmosphere. Bromine tribromide (0.9 g, 3.6 mmol, 3.6 mL) wasadded and the reaction was run at room temperature for two days. Thereaction mixture was concentrated and chromatographed on a silica gelcolumn eluting with 3% MeOH saturated with ammonia in CH₂ Cl₂ to give anoff white borate salt solid (0.14 g, 61% yield, MH⁺ 446).

EXAMPLE 246 1-1(4-PYRIDINYLACETYL)-4-3-BROMO8-CHLORO5-6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11YLIDENE!-PIPERIDINE ##STR524##

By essentialy the same procedure as set forth in Example 180 but using4-(3-bromo-8-chloro-5,6-dihydro-11H-benzo5,6!cyclohepta(1,2-b!pyridin-11-ylidene)-piperidine instead of4-(3,8-dichloro-5,6-dihydro-11H-benzo-5,6!cyclohepta(1,2-b!pyridin-11-ylidene)-piperidine, the title compoundwas obtained as a glassy solid (MH⁺ 508).

EXAMPLE 247 1-1(3-PYRIDINYLACETYL)-4-3-BROMO8-CHLORO5-6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11YLIDENE!-PIPERIDINE ##STR525##

By essentialy the same procedure as set forth in Example 180, but using4-(3-bromo-8-chloro-5,6-dihydro-11H-benzo5,6!cyclohepta(1,2-b!pyridin-11-ylidene)-piperidine instead of4-(3,8-dichloro-5,6-dihydro-11H-benzo 5,6!cyclohepta1,2-b!pyridin-11-ylidene)-piperidine and 3-pyridyl acetic acid insteadof 4-pyridyl acetic acid, the title compound was obtained as a whitesolid (mp=92°-93° C. MH⁺ 508).

EXAMPLE 248 4- 4,8-DICHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-1-(4-PYRIDINYLACETYL)-PIPERIDINE and 4-2,8-DICHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-1-(4-PYRIDINYLACETYL)-PIPERIDINE ##STR526##

A solution of the title compound from Example 230 (1.7 grams) andphosphorous oxychloride (21 mL) dissolved in chloroform (12 mL) wasstirred at reflux for 1 hour. Concentration in vacuo provided a residuewhich was diluted with CH₂ Cl₂ and washed with saturated aqueous sodiumbicarbonate and brine. The organic phase was dried over anhydrous MgSO₄,concentrated in vacuo, and purified by flash column chromatography(silica gel) using 2% MeOH-CH₂ Cl₂ to afford the title 4,8-dichlorocompound (0.34 grams, 20% yield, mp 84°-91° C., MH⁺ 464) and the title2,8-dichloro compound (0.18 grams, 11% yield, mp 163.8°-164.6° C., MH⁺464).

EXAMPLE 249 4- 4-(1H-BENZOTRIAZOL-1-YL)OXY!-8-CHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-1-(4-PYRIDINYLACETYL)-PIPERIDINE ##STR527##

A mixture of the 4,8-dichloro compound from Example 248 (0.5 grams),HOBT hydrate (0.4 grams) and anhydrous DMF (20 mL) was stirred at 25° C.under N₂ for 5 days. The mixture was concentrated in vacuo, diluted withCH₂ Cl₂, and washed with 1N aqueous NaOH. The organic phase was driedover anhydrous MgSO₄, concentrated in vacuo and purified by flash columnchromatography (silica gel) using 3-5% MeOH-CH₂ Cl₂ to give the titlecompound (0.58 grams, 96%, mp 98.6°-101.6° C., MH⁺ 563).

EXAMPLE 250 4- 4,8-DICHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-1-(3-PYRIDINYLACETYL)-PIPERIDINE ##STR528##

A mixture of the 4,8-dichloro product from Preparative Example 28 (1.91grams), 3-pyridylacetic acid hydrochloride (2.1 grams), DEC (1.6 grams),4-methylmorpholine (1.4 mL) and anhydrous DMF (100 mL) was stirred at25° C. overnight. Concentration in vacuo provided a residue which wasdiluted with CH₂ Cl₂ and water. The organic phase was dried overanhydrous MgSO₄ and concentrated in vacuo to provide the title compound(2.2 grams, 87%, mp 59.8°-63.5° C., MH⁺ 464).

EXAMPLE 251 4- 4-(1H-BENZOTRIAZOL-1-YL)OXY!-8-CHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-1-(3-PYRIDINYLACETYL)-PIPERIDINE ##STR529##

The 4,8-dichloro compound from Example 250 (0.8 grams) was added to asolution of HOBT (1.2 grams) and sodium hydride (0.14 grams, 60% inmineral oil) in anhydrous dimethyl-formamide (60 mL). The resultingsolution was irradiated with a 200 W lamp while stirring at 25° C. for60 hours. The solution was poured into 1N aqueous NaOH while stirringand an additional 400 mL of water was added to the resulting mixture.Filtration provided a solid which was washed with water several times.The solid was dissolved in CH₂ Cl₂ -acetone, dried over anhydrous MgSO₄,and concentrated in vacuo to proved the title compound (0.87 grams, 90%,mp=120°-122° C., MH⁺ 563).

EXAMPLE 252 4- 4-HYDROXY-8-CHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-1-(3-PYRIDINEYLACETYL)-PIPERIDINE ##STR530##

To a solution of the title compound form Example 251 (0.8 grams) andglacial acetic acid (30 mL) was added zinc dust (0.4 grams). Afterstirring at 25° C. for 18 hour, the mixture was filtered through celiteand the filtrate concentrated in vacuo. The residue was diluted withEtOAc, washed with saturated aqueous sodium bicarbonate and brine. Theorganic layer was separated, dried over MgSO₄ and concentrated in vacuoto give the title compound (Yield 0.346 grams, 58%, MH+ 446).

EXAMPLE 253 4- 3-BROMO-4-HYDROXY-8-CHLORO-5,6-DIHYDRO-11H-BENZO5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-1-(3-PYRIDINYLACETYL)-PIPERIDINE ##STR531##

To a solution of the title compound from Example 252 (0.19 grams) andglacial acetic acid (4 mL) was added a 0.7M bromine-acetic acid solution(0.7 mL) at 25° C. under N₂. After 10 minutes, water was added and theresulting solid was filtered and washed with water several times anddried to give the title compound (0.18 grams, 71%, MH⁺ 526).

EXAMPLE 255 4- 8-CHLORO-4-(METHYLTHIO)-5,6-DIHYDRO-11H-BENZO5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-1-(3-PYRIDINYLACETYL)-PIPERIDINE ##STR532##

A mixture of the title compound from Example 250 (0.26 grams), sodiummethylthiolate (0.06 grams) and anhydrous DMF (10 mL) was stirred whilebeing irradiated with a 200 W lamp for 1 hour. After stirring anadditional 12 hours at room temperature without irradiation, the mixturewas concentrated in vacuo, diluted with CH₂ Cl₂, and washed with 1Naqueous NaOH and brine. The organic phase was dried over anhydrous MgSO₄and concentrated in vacuo to afford the title compound as a white foam(0.3 grams, 100%, MH⁺ 476).

EXAMPLE 256 4- 8-CHLORO-4-(METHYLSULFINYL)-5,6-DIHYDRO-11H-BENZO5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-1-(3-PYRIDINYLACETYL)-PIPERIDINE ##STR533##

To the title compound from Example 255 (0.18 grams) dissolved inanhydrous THF (10 mL) was added 30% aqueous hydrogen peroxide (3 mL) andthe resulting solution was stirred for 12 hours at 73° C. The solutionwas concentrated in vacuo, diluted with CH₂ Cl₂, and washed with water.The organic phase was dried over anhydrous MgSO₄ and concentrated invacuo to afford the title compound after preparative platechromatography (silica gel) using 3% MeOH-CH₂ Cl₂ (0.04 grams, 26%, MH⁺492).

EXAMPLE 257 METHYL 8-CHLORO-6,11-DIHYDRO-11- 1-1-OXO-2-(3-PYRIDINYL)ETHYL!-4-PIPERIDINYLIDENE!-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-4-YL!THIO!ACETATE ##STR534##

A mixture of the title compound from Example 250 (0.26 grams), sodiumhydride (0.08 grams, 60% in mineral oil), methyl thioglycolate (0.19 mL)and anhydrous DMF (15 mL) was stirred while being irradiated with a 200W lamp for 16 hours. The mixture was diluted with MeOH, concentrated invacuo, diluted with CH₂ Cl₂ and water, and washed with 1N aqueous NaOHand brine. The organic phase was dried over anhydrous MgSO₄ andconcentrated in vacuo and the residue purified by preparative platechromatography (silica gel) using 3% MeOH-CH₂ Cl₂ to afford the titlecompound (0.05 grams, 15%, MH⁺ 534).

EXAMPLE 258 4- 8-CHLORO-5,6-DIHYDRO-4-(PHENYLMETHYLTHIO)-11H-BENZO5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-1-(3-PYRIDINYLACETYL)-PIPERIDINE ##STR535##

A mixture of the title compound from Example 250 (0.25 grams), sodiumhydride (0.11 grams, 60% in mineral oil), benzyl mercaptan (0.13 mL) andanhydrous DMF (15 mL) was stirred while being irradiated with 200 W lampfor 10 days. Isolation and purification as in Example 257 provided thetitle compound (0.02 grams, 8%, MH⁺ 552).

EXAMPLE 259 4- 8-CHLORO-5,6-DIHYDRO-4-(2-METHYL-2H-TETRAZOL-5-YL)THIO!-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-1-(3-PYRIDINYLACETYL)-PIPERIDINE ##STR536##

A mixture of the title compound from Example 250 (0.24 grams),5-mercapto-1-methyltetrazole sodium salt (0.6 grams) and anhydrous DMF(10 mL) was stirred while being irradiated with a 200 W lamp for 10days. Isolation and purification as in Example 257 provided the titlecompound (0.2 grams, 68%, MH⁺ 544).

EXAMPLE 260 1,1-DIMETHYLETHYL 2- 8-CHLORO-6,11-DIHYDRO-11- 1-1-OXO-2-(3-PYRIDINYL)ETHYL!-4-PIPERIDINYLIDENE!-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-4-YL!THIO!ETHYL!CARBAMATE ##STR537##

A mixture of the title compound from Preparative Example 32 (0.032grams), 3-pyridylacetic acid hydrochloride (0.05 grams), DEC (0.03grams), Et₃ N (0.08 mL) and anhydrous DMF (4 mL) was stirred at 25° C.for 48 hours. Concentration in vacuo provided a residue which wasdiluted with CH₂ Cl₂ and washed with 1N aqueous NaOH. The organic phasewas dried over anhydrous MgSO₄ and concentrated in vacuo to provide thetitle compound (0.02 grams, 50%, mp 59.8°-63.5° C., MH⁺ 605).

EXAMPLE 261 4-(4,8-DICHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIRIDIN-11-YLIDENE)-N-(3-PYRIDYL)-1-PIPERIDINECARBOXAMIDE##STR538##

A portion of the stock solution of 3-pyridylisocyanate (32 mL) preparedas described in Preparative Example 33 was added to the 4,6-dichloroproduct from Preparative Example 28 (1.37 grams) and the mixture wasstirred at 25° C. for 4 days. The mixture was evaporated to dryness andthe residue was taken up in CH₂ Cl₂ and washed with saturated aqueoussodium bicarbonate and then water. The organic solution was dried overMgSO₄, filtered and evaporated to dryness. The residue was purified byflash column chromatography silica gel) using 2% MeOH-CH₂ Cl₂ as eluentto give the title compound (Yield 1.25 grams, 70%, MH+ 465).

EXAMPLE 262 4- 4-(1H-BENZOTRIAZOL-1-YL)OXY!-8-CHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-N-(3-PYRIDYL)-1-PIPERIDINECARBOXAMIDE##STR539##

To a solution of the title compound from Example 261 (1.0 grams) in dryDMF (60 mL) was added HOBT (1.4 grams), sodium hydride (0.2 grams, 60%in mineral oil) and distilled water (0.5 mL). The solution was stirredat 25° C. under nitrogen while being irradiated with a 200 Watt lamp for20 hours. The reaction mixture was concentrated in vacuo, diluted withCH₂ Cl₂ and saturated aqueous sodium bicarbonate and after two hours,the organic phase was separated, dried over MgSO₄ and concentrated.Purification by flash column chromatography (silica gel) using 3-5%MeOH-CH₂ Cl₂ afforded the title compound (Yield 1.1 grams, 87%, MH+564).

EXAMPLE 263 4- 4-HYDROXY-8-CHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-N-(3-PYRIDYL)-1-PIPERDINECARBOXAMIDE##STR540##

To a solution of the title compound form Example 262 (0.86 grams) andglacial acetic acid (20 mL) was added zinc dust (0.5 grams). Afterstirring at 25° C. for 1.5 hours, the mixture was filtered throughcelite and the filtrate concentrated in vacuo. The residue was purifiedby flash column chromatography (silica gel) using 5-10% MeOH-CH₂ Cl₂saturated with ammonium hydroxide to give the title compound (Yield 0.47grams, MH+448).

EXAMPLE 264 4- 3-BROMO-4-HYDROXY-8-CHLORO-5,6-DIHYDRO-11H-BENZO5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-N-(3-PYRIDYL)-1-PIPERIDINECARBOXAMIDE##STR541##

To a solution of the title compound from Example 263 (0.34 grams) andglacial acetic acid (10 mL) was added a 0.7M bromine-acetic acidsolution (4 mL) at 25° C. under N₂. After 10 minutes, water was addedand the resulting solid was filtered and washed with water several timesand dried to give the title compound (Yield 0.31 grams, 67%, MH⁺ 527).

EXAMPLE 266 4-(8-CHLORO-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YL)-1-(3-PYRIDINYLACETYL)-PIPERIDINE ##STR542##

The title compound from Preparative Example 34C (2.0 g, 6.4 mmole) wasdissolved in anhydrous DMF (70 mL) and the solution was cooled with anice bath for 30 minutes. 4-Methylmorpholine (3.3 g, 32 mmole), DEC (1.8g, 9.7 mmole) and HOBT (0.87 g 6.4 mmole) were added to the coldsolution. 3-Pyridylacetic acid (0.88 g, 6.4 mmole) was added and thecooling bath removed. Stir the mixture at room temperature for 18 hours.The reaction mixture was evaporated to dryness and the residue wasdiluted with water (50 mL). The aqueous mixture was extracted with EtOAcand the combined extracts dried (MgSO₄), filtered and evaporated. Theresulting residue was purifed by silica gel chromatography using agradient of 97% CH₂ Cl₂ /3% MeOH saturated with ammonia to 93%dichlormethane/7% MeOH saturated with ammonia as eluent to give thetitle compound (0.87 g MH⁺ 430).

EXAMPLE 267 E. 4-(8-CHLORO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YL)-N-(3-PYRIDINYL)-1-PIPERIDINECARBOXAMIDE ##STR543##

The title compound from Preparative Example 34C was treated with3-pyridylisocyanate, similar to the procedure in Example 261, to affordthe title compound (MH⁺ 431).

EXAMPLE 268 4-(8-CHLORO-5H-BENZO 5,6!CYCLOHEPTA 1,2-b!PYRIDIN-11-YL)-1-2-METHYL-2-(3-PYRIDINYL)-1-OXOPROPYL!-PIPERIDINE ##STR544##

The title compound from Preparative Example 34C was treated as describedin Example 266, using α,α-dimethyl-3-pyridylacetic acid (described inPreparative Example 10B) in place of 3-pyridylacetic acid, to afford thetitle compound (M+ 458),

EXAMPLE 269 4-(8-CHLORO-5 H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YL)-1-(4-PYRIDINYLACETYL)-PIPERIDINE ##STR545##

The title compound from Preparative Example 34C above was treated asdescibed in Example 266, using 4-pyridylacetic acid in place of3-pyridylacetic acid, to give the title compound (M⁺ 430).

EXAMPLE 270 4-(8-CHLORO-9-ETHYL-5H-BENZO 5,6!CYCLOHEPTA-1,2-b!PYRIDIN-11-YL)-1-(3-PYRIDINYLACETYL)-PIPERIDINE ##STR546##

The title compound from Preparative Example 2A was treated as descibedin Example 266 to give the title compound (M+=458, mp=67.2°-69.8° C.).

EXAMPLE 273 4-(4,8-DiCHLORO-5H-BENZO 5,6!CYCLOHEPTA1,2-B!PYRDIN-11-YL)-1-(3-PYRIDINYLACETYL)-PIPERIDINE ##STR547##

The title compound from Preparative Example 36C was treated as descibedin Example 266 to give the title compound (mp 100.1°-103.4° C.).

EXAMPLE 274 4-(4,8-DICHLORO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YL)-N-(3-PYRIDINYL)-1-PIPERIDINECARBOXAMIDE ##STR548##

The title compound from Preparative Example 36C (0.75 g, 2.17 mmol) wastreated with a pyridine solution of 3-pyridylisocyanate (fromPreparative Example 33). The reaction mixture was evaporated to drynessand the residue dissolved in CH₂ Cl₂. This solution was washed withsaturated sodium bicarbonate solution and brine, dried (MgSO₄), filteredand evaporated to give a dark syrup. The syrup was purified by silicagel chromatography using a gradient of 97% CH₂ Cl₂ /3% MeOH saturatedwith ammonia to 93% CH₂ Cl₂ /7% MeOH saturated with ammonia. The titlecompound was obtained as a yellow solid (0.13 g, M+ 465)

EXAMPLE 276 4-(8-CHLORO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11YLIDENE)-1-(3-PYRIDINYLACETYL)-PIPERIDINE ##STR549##

The title compound from Preparative Example 37B was treated as descibedin Example 266 to give the title compound (MH⁺ 428).

EXAMPLE 277 4-(8CHLORO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11YLIDENE)-N-(3-PYRIDINYL)-1-PIPERIDINECARBOXAMIDE##STR550##

The title compound from Preparative Example 37B above was treated asdescibed in Example 261 above to give the title compound (mp 95.9°-97.6°C.).

EXAMPLE 278 4-(8-CHLORO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11YLIDENE)-1-2-METHYL-2-(3-PYRIDINYL)-1-OXO-PROPYL!-PIPERDINE ##STR551##

The title compound from Preparative Example 37B was treated as descibedin Example 266 using α,α-dimethyl-3-pyridylacetic acid (described inPreparative Example 10B) in place of 3-pyridylacetic acid, to give thetitle compound (M+ 456).

EXAMPLE 279 4-(8-CHLORO-5,6-DIHYDROXY-5-OXO-11H-BENZO 5,6!-CYCLOHEPTA1,2-b!PYRIDIN-11YLIDENE)-1-(3-PYRIDINYLACETYL)-PIPERIDINE ##STR552##

The preparation of the starting material for this reaction was describedin The Journal of Organic Chemistry, 1990, 55, pp. 3341-3350 byPiwinski, J. J.; Wong, J. K.; Chan, T.-M.; Green, M. J.; and Ganguly, A.K. The procedure described in Example 266 was followed using8-chloro-6,11-dihydro-11-(4-piperidinylidene)-5H-benzo 5,6!cyclohepta1,2-b!pyridin-5-one to give the title compound (M⁺ 443).

EXAMPLE 280 4-(8-CHLORO-5,6-DIHYDRO-5-HYDROXY-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11YLIDENE)-1-(3-PYRIDINYLACETYL)-PIPERIDINE ##STR553##

The preparation of the starting material for this reaction was describedin The Journal of Organic Chemistry, 1990, 55, pp. 3341-3350 byPiwinski, J. J.; Wong, J. K.; Chan, T.-M.; Green, M. J.; and Ganguly, A.K. The procedure described in Example 266 was followed using8-chloro-6,11-dihydro-5-hydroxy-11-(4-piperidinylidene)-5H-benzo5,6!cyclohepta 1,2-b!pyridine to give the title compound (MH⁺ 446).

EXAMPLE 281 4-(8-CHLORO-5,6-DIHYDRO-5-OXO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11YLIDENE)-1-(4-PYRIDINYLACETYL)-PIPERIDINE ##STR554##

The procedure of Example 279 was followed with the exception that4-pyridylacetic acid was used in place of 3-pyridylacetic acid to givethe title compound (MH⁺ 444).

EXAMPLE 282 4-(8-CHLORO-5,6-DIHYDRO-5-HYDROXY-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11YLIDENE)-1-(4-PYRIDINYLACETYL)-PIPERIDINE ##STR555##

The procedure of Example 280 was followed with the exception that4-pyridylacetic acid was used in place of 3-pyridylacetic acid to givethe title compound (MH⁺ 446).

EXAMPLE 283 4-(8-CHLORO-5,6-DIHYDRO-6-OXO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11YLIDENE)-1-(3-PYRIDINYLACETYL)-PIPERIDINE ##STR556##

The preparation of the starting material for this reaction was describedin The Journal of Organic Chemistry, 1990, 55, pp. 3341-3350 byPiwinski, J. J.; Wong, J. K.; Chan, T.-M.; Green, M. J.; and Ganguly, A.K. The procedure described in Example 266 was followed using8-chloro-6,11-dihydro-11-(4-piperidinylidene)-5H-benzo 5,6!cyclohepta1,2-b!pyridin-6-one to give the title compound (M⁺ 444).

EXAMPLE 284 4-(8-CHLORO-5,6-DIHYDRO-6-HYDROXY-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11YLIDENE)-1-(3-PYRIDINYLACETYL)-PIPERIDINE ##STR557##

The preparation of the starting material for this reaction was describedin The Journal of Organic Chemistry, 1990, 55, pp. 2241-3350 byPiwinski, J. J.; Wong, J. K.; Chan, T.-M.; Green, M. J.; and Ganguly, A.K. The procedure described in Example 266 above was followed using8-chloro-6,11-dihydro-6-hydroxy-11-(4-piperidinylidene)-5H-benzo5,6!cyclohepta 1,2-b!pyridine to give the title compound (MH⁺ 446).

EXAMPLE 285 4-(8-CHLORO-5,6-DIHYDRO-6-OXO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11YLIDENE)-1-(4-PYRIDINYLACETYL)-PIPERIDINE ##STR558##

The procedure of Example 283 was followed with the exception4-pyridylacetic acid was used in place of 3-pyridylacetic acid to givethe title compound (M⁺ 444).

EXAMPLE 286 4-(8-CHLORO-5,6-DIHYDRO-6-HYDROXY-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11YLIDENE)-1-(4-PYRIDINYLACETYL)-PIPERIDINE ##STR559##

The procedure of Example 284 was followed with the exception that4-pyridylacetic acid was used in place of 3-pyridylacetic acid to givethe title compound (MH⁺ 446).

EXAMPLES 287, 289 AND 290

By essentially the same procedure as in Example 1, but using either(R)-(+)-α-methoxy-α-(trifluromethyl)-phenylacetic acid (Example 290),(S)-(-)-α-methoxy-α-(trifluromethyl)-phenylacetic acid (Example 287), orα,α-dimethylphenylacetic acid (Example 289), the compounds of Example290, 287 and 289 were obtained. The structures for these compounds arein Table 7. Data for these compounds are: compound of Example 290, whitesolid MH+ 527; compound of Example 287, white solid MH+ 527; andcompound of Example 289, white solid M+ 457.

EXAMPLES 291, 292, 294, 313 AND 314

By essentially the same procedure as in Example 183, and using either4-, 3-, or 2-ethoxycarbonylaminopyridine and either4-(8-chloro-5,6-dihydro-11H-benzo 5,6!cyclohepta1,2-b!pyridin-11-ylidene)piperidine or8-chloro-6,11-dihydro-11-(4-piperidinyl)-5H-benzo 5,6!cyclohepta1,2-b!pyridine (product of Example 233A), the compounds of Examples 291,292, 294, 313 and 314 were obtained. The structures for the compounds ofExamples 291, 292, and 294 are given in Table 7. The structures for thecompounds of Examples 313 and 314 are given in Table 10. Data are: thecompound of Example 291 was a yellow solid (MH⁺ 431), the compound ofExample 292 was an off white solid (MH⁺ 431), the compound of Example294 was an off white solid (MH⁺ 431), the compound of Example 313 was awhite solid (MH⁺ 433), and the compound of Example 314 was a white solid(MH⁺ 433).

EXAMPLE 301 1-1-(4-PYRIDINYLACETYL)-4-3-METHYL-8-CHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-PIPERIDINE ##STR560##

By essentially the same procedure as set forth in Example 180, but using4-(8-chloro-3-methyl-5,6-dihydro-11-(4-piperidylidene)-11H-benzo5,6!cyclohepta 1,2-b!pyridine (from Preparative Example 3E) instead of4-(3,8-dichloro-5,6-dihydro-11-(4-piperidylidene)-11H-benzo5,6!cyclohepta 1,2-b!pyridine, the title compound was obtained as anoff-white solid MH+ 444

EXAMPLE 303 1-1-(3-PYRIDINYLACETYL)-4-3-METHYL-8-CHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-PIPERIDINE ##STR561##

By essentially the same procedure as set forth in Example 180, but using4-(8-chloro-3-methyl-5,6-dihydro-11-(4-piperidylidene)-11H-benzo5,6!cyclohepta 1,2-b!pyridine (from Preparative Example 3E) instead of4-(3,8-dichloro-5,6-dihydro-11-(4-piperidylidene)-11H-benzo5,6!cyclohepta 1,2-b!pyridine, and 3-pyridylacetic acid instead of4-pyridylacetic acid, the title compound was obtained as white solid MH+444.

EXAMPLE 307

By essentially the same procedure as in Example 1, using the titlecompound from Preparative Example 37B, and 4-pyridylacetic acid thecompound of Example 307, identified in Table 8, was obtained, MH⁺ 428.

EXAMPLE 309 1-1-(4-PYRIDINYLACETYL)-4-2-METHYL-8-CHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-PIPERIDINE ##STR562##

By essentially the same procedure as set forth in Example 180, but using4-(8-chloro-2-methyl-5,6-dihydro-11-(4-piperidylidene)-11H-benzo5,6!cyclohepta 1,2-b!pyridine (from Preparative Example 3E) instead of4-(3,8-dichloro-5,6-dihydro-11-(4-piperidylidene)-11H-benzo5,6!cyclohepta 1,2-b!pyridine, and 3-pyridylacetic acid instead of4-pyridylacetic acid, the title compound was obtained as white solid MH+444.

EXAMPLE 311 1-1-(4-PYRIDINYLACETYL)-4- 8,9DICHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-PIPERIDINE ##STR563##

By essentially the same procedure as set forth in Example 180, but using4-(8,9-dichloro-5,6-dihydro-11-(4-piperidylidene)-11H-benzo5,6!cyclohepta 1,2-b!pyridine (from Preparative Example 1H) instead of4-(3,8-dichloro-5,6-dihydro-11-(4-piperidylidene)-11H-benzo5,6!cyclohepta 1,2-b!pyridine, and 3-pyridylacetic acid instead of4-pyridylacetic acid, the title compound was obtained as white solid MH+464.

EXAMPLE 312

By essentially the same procedure as in Example 182, with the exceptionthat 8-chloro-6,11-dihydro-11-(4-piperidinyl)-5H-benzo 5,6!cyclohepta1,2-b!pyridine is used instead of8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo 5,6!cyclohepta1,2-b!pyridine, the compound of Example 312 was obtained as a whitesolid (MH⁺ 432). The structure for this compound is given in Table 10.

EXAMPLE 350 8-CHLORO-11H-BENZO 5,5!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE)-4-(3-PYRIDINYLACETYL)PIPERAZINE ##STR564##

By substituting in Example 75, 0.4 g (1.28 mmoles) of8-chloro-11-(1-piperazinyl)-11H-benzo 5,6!cyclohepta 1,2-b!pyridine(Preparative Example 38) for8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo 5,6!cyclohepta1,2-b!pyridine and 0.1765 g (1.28 mmoles) of 3-pyridylacetic acid for4-pyridylacetic acid and using the same method as described in Example75, one obtains the title compound (0.513 g, 93%, MH⁺ 431).

EXAMPLE 351 1-(3-BROMO-8-CHLORO-6,11-DIHYDRO-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YL)-4-(3-PYRIDINYLACETYL)PIPERAZINE ##STR565##

By substituting in Example 75,3-bromo-8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo 5,6!cyclohepta1,2-b!pyridine (0.32 g, 0.81 mmoles) (Preparative Example 40) for8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo 5,6!cyclohepta1,2-b!pyridine and 3-pyridylacetic acid (0.117 g, 0.86 mmoles) for4-pyridylacetic acid and using the method described in Example 75, oneobtains the title compound (0.3942 g, 95%, MH⁺ 511).

EXAMPLES 352-353

By essentially the same procedures as set forth in Example 351, butusing ##STR566## in place of 3-pyridylacetic acid, one obtains compoundsof the formulas ##STR567## respectively. The compound of Example 352 isa white amorphous solid, yield 65%, Mass Spec MH⁺ 555. The compound ofExample 353 is a white amorphous solid, yield 59%, Mass Spec MH⁺ 539.

EXAMPLE 354 4-(3-BROMO 8-CHLORO-6,11-DIHYDRO-5H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YL)-N-(3-PYRIDINYL)-1-PIPERAZINECARBOXAMIDE ##STR568##

The title compound from Preparative Example 40 (0.37 g, 0.94 mmoles) wasreacted with 3-ethoxycarbonylaminopyridine (Preparative Example 12)(0.123 g, 0,94 mmoles) under essentially the same conditions asdescribed in Example 183, to give the title compound (0.3164 g, 66%, MH⁺512).

EXAMPLE 355 1-(4,8-DICHLORO-6,11-DIHYDRO-5H-BENZO 5,6!CYCLOHEPTA1,2-b!-PYRIDIN-11-YL)-4-(3-PYRIDYLACETYL)PIPERAZINE ##STR569##

By substituting in Example 75,4,8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo 5,6!cyclohepta1,2-b!pyridine (0.3 g, 0.86 mmoles) (Preparative Example 41) for8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo 5,6!cyclohepta1,2-b!pyridine and 3-pyridylacetic acid (0.1181 g, 0.86 mmoles) for4-pyridylacetic acid and using the method described in Example 75 ,oneobtains the title compound (0.357 g, 88%, MH⁺ 467).

EXAMPLE 356 4- 3-BROMO-4,8-DICHLORO-5,6-DIHYDRO-11H-BENZO 5,6!CYCLOHEPTA1,2-b!PYRIDIN-11-YLIDENE!-1-(4-PYRIDINYLACETYL)-PIPERIDINE ##STR570##

A mixture of the title compound from Preparative Example 46 (0.68grams), 4-pyridylacetic acid hydrochloride (0.60 grams), DEC (0.65grams), 4-methyl-morpholine (0.6 mL) and anhydrous DMF (20 mL) wasstirred at 25° C. for 48 hours. Concentration in vacuo provided aresidue which was diluted with CH₂ Cl₂ and washed with 1N aqueous NaOHand brine. The organic phase was dried over anhydrous MgSO₄ andconcentrated in vacuo to provide a residue which was purified by flashcolumn chromatography (silica gel) using 2-5% MeOH-CH₂ Cl₂ saturatedwith ammonium hydroxide to afford the title compound (0.06 grams, 7%,MH⁺ 544).

EXAMPLE 358 A.4-(8-CHLORO-3-NITRO-5,6-DIHYDRO-11-(4-PIPERIDYLIDENE)-11H-BENZO5,6!CYCLOHEPTA 1,2-b!PYRIDINE, ##STR571##

Hydrolyze the title compound of Preparative Example 47A (10.0 g, mmol)by dissolving in conc. HCl (250 mL) and heating to 100° C. for 16 h. Thecooled acidic mixture was neutralized with 1M NaOH (950 mL). The mixturewas extracted with CH₂ Cl₂. The latter was dried over MgSO₄. Filtrationand concentration afforded the title compound in 99% yield as a solid.MH+ 358.

B. 1-1-(4-PYRIDINYLACETYL)-4- 3-BROMO-8-CHLORO-5,6-DIHYDRO-11H-BENZO5,6!CYCLOHEPTA 1,2-b!PYRIDIN-11-YLIDENE!-PIPERIDINE ##STR572##

By essentially the same procedure as set forth in Example 180, but using4-(8-chloro-3-nitro-5,6-dihydro-11-(4-piperidylidene)-11H-benzo5,6!cyclohepta 1,2-b!pyridine instead of4-(3,8-dichloro-5,6-dihydro-11-(4-piperidylidene)-11H-benzo5,6!cyclohepta 1,2-b!pyridine, the title compound was obtained as anoff-white solid. Mp=111.3°-112.2° C., MH+ 475.

EXAMPLE 400 ##STR573##

The product of Preparative Example 48, Step B, is reacted with 4-pyridylacetic acid via essentially the same procedure as described in Example180 to give the product compound (5.210). Mass Spec.: MH⁺ =556

Using the appropriate carboxylic acid and the starting compoundindicated, the following compounds were prepared via substantially thesame procedure as described for Example 400:

    __________________________________________________________________________    Starting                      Analytical                                      Compound                                                                             Product Compound       Data                                            __________________________________________________________________________    Preparative Example 49                                                                ##STR574##            Mass Spec.: MH.sup.+  = 458                     Preparative Example 53C                                                               ##STR575##            Mass Spec.: MH.sup.+  = 528.2                   Preparative Example 53C                                                               ##STR576##            Mass Spec.: MH.sup.+  = 524.2                   Preparative Example 53C                                                               ##STR577##            Mass Spec.: MH.sup.+  = 524.1                   Preparative Example 51A                                                               ##STR578##            Mass Spec.: MH.sup.+  = 512.1                   Preparative Example 51A                                                               ##STR579##            Mass Spec.: MH.sup.+  = 528                     Preparative Example 53C                                                               ##STR580##            Mass Spec.: MH.sup.+  = 508.0                   Preparative Example 49                                                                ##STR581##            Mass Spec.: MH.sup.+  = 530.2                   Preparative Example 51A                                                               ##STR582##            Mass Spec.: MH.sup.+  = 532.3                   Preparative Example 49                                                                ##STR583##            Mass Spec.: MH.sup.+  = 530.2                   Preparative Example 49                                                                ##STR584##            Mass Spec.: MH.sup.+  = 526                     Preparative Example 56 Step C                                                         ##STR585##            Mass Spec.: MH.sup.+  = 581                     Preparative Example 49                                                                ##STR586##            Mass Spec.: MH.sup.+  = 449.2                   Preparative Example 51A                                                               ##STR587##            m,p. = 62.8°-63.5° C. Mass                                      Spec.: MH.sup.+  = 451                          Preparative Example 53B                                                               ##STR588##            Mass Spec.: MH.sup.+  = 602                     __________________________________________________________________________

EXAMPLE 401 ##STR589##

The product of Preparative Example 48, Step B, is reacted with 4-pyridylacetic acid N-oxide via essentially the same procedure as described inExample 227 to give the product compound (5.209). Mass Spec.: MH⁺ =572

Using the appropriate carboxylic acid and the starting compoundindicated, the following compounds were prepared via substantially thesame procedure as described for Example 401:

    ______________________________________                                        Starting                       Analytical                                     Compound                                                                              Product Compound       Data                                           ______________________________________                                        Preparative Example 50                                                                 ##STR590##            Mass Spec.: MH.sup.+  = 462                    ______________________________________                                    

EXAMPLE 402 ##STR591##

The product of Example 358, Step B, is reduced via essentially the sameprocedure as described in Step B of Preparative Example 47 to give theproduct compound. mp=133.2°-133.4° C. MH⁺ 445

Using the starting compound indicated, the following compounds wereprepared via substantially the same procedure as described for Example402:

    ______________________________________                                        Starting                                                                      Com-                           Analytical                                     pound  Product Compound        Data                                           ______________________________________                                        Example 411-B                                                                         ##STR592##             Mass Spec.: MH.sup..sup.+  = 445.2             ______________________________________                                    

EXAMPLE 403 ##STR593##

Combine 0.3 g (0.67 mmol) of the product of Example 402, 5 mL ofpyridine and 0.1 g (1.01 mmol) of acetic anhydride and stir the mixtureat room temperature for 2 days. Add another 100 μL of acetic anhydride,warm to 60° C. and stir for 6 h. Neutralize the reaction mixture thenbasify with 1N NaOH (aqueous) to pH=10. Extract with CH₂ Cl₂, dry theextract over MgSO₄ and concentrate to a residue. Purify the residue byHPLC eluting 8% MeOH/CH₂ Cl₂ +concentrated NH₄ OH (aqueous) to give 0.22g of the product compound. Mass Spec.: MH⁺ =487

EXAMPLE 404 ##STR594##

The product of Example 402 is reacted with methanesulfonyl chloride viasubstantially the same procedure as described for Example 403 to givethe 0.32 g of the product compound. Mass Spec.: MH⁺ =523

EXAMPLE 405 ##STR595##

Combine 1.5 g (3.37 mmol) of the product of Example 402 and 10 mL ofAcOH, then add 3.37 mL of a solution of bromine in AcOH and stir themixture at room temperature overnight. Basify the mixture with 1N NaOH(aqueous) to basic pH, then extract with EtOAc. Concentrate the extractto a residue and chromatograph (silica gel, 90% EtOAc/hexane, then 5%Et₃ N/EtOAc) to give the product compound. Mass Spec.: MH⁺ =525.

EXAMPLE 406 ##STR596##

Combine 0.5 g (1.12 mmol) of the product of Example 402 and 10 mL ofacetone, add 230 μL of conc. HCl (aqueous) and 4 mL of water, and coolto -10° C. Add a solution of 0.085 g NaNO₂ in 4 mL of water, stir for 15min., then add the reaction mixture to a solution of CuCN freshlyprepared by adding 0.336 g (1.34 mmol) of CuSO₄ in 2 mL of water to H₂ Oa solution of 0.365 g (5.6 mmol) of KCN in 2 mL of H₂ O!. Heat themixture to 60°-70° C., then at 70°-80° C. to remove acetone. Cool themixture and dilute with H₂ O, then exhaustively extracted with CH₂ Cl₂.Concentrate the extracts to a residue then purify by HPLC using 3%methanolic ammonia in CH₂ Cl₂ to give 0.25 g (50% yield) of the productcompound. Mass Spec.: MH⁺ =455.

EXAMPLE 407 ##STR597##

Combine 0.55 g (1.25 mmol) of the product of Example 402 and 50 mL ofdilute H₂ SO₄ at room temperature. Cool the mixture to -10° C., add asolution of 0.092 g of NaNO₂ in 5 mL of water was added and stir for 15min. Slowly add a solution of 0.46 g (4.7 mmol) of KSCN and 0.3 g (2.49mmol) of CuSCN in 15 mL of water over a period of 0.5 hours. Stir for0.5 hour then heat at reflux for 15 min. Cool the mixture and adjust thepH to ˜7, then extract with CH₂ Cl₂. Concentrate the extracts to aresidue and chromatograph (silica gel, 3% MeOH/CH₂ Cl₂ +NH₄ OH) to givethe product compound. Mass Spec.: MH⁺ =487

EXAMPLE 410 ##STR598##

The product of Preparative Example 50 was reacted with 4-pyridylaceticacid via substantially the same procedure as described for Example 180to give the product compound. Mass Spec.: MH⁺ =446

Using the appropriate carboxylic acid and the starting compoundindicated, the following compounds were prepared via substantially thesame procedure as described for Example 410:

    __________________________________________________________________________    Starting                            Analytical                                Compound                                                                             Product Compound             Data                                      __________________________________________________________________________    Preparative Example 49A                                                               ##STR599##                  Mass Spec.: MH.sup.+  = 526               Preparative Example 49A                                                               ##STR600##                  Mass Spec.: MH.sup.+  = 542               Preparative Example 49A                                                               ##STR601##                  Mass Spec.: MH.sup.+  = 542               Preparative Example 52                                                                ##STR602##                  m.p. = 67°-69° C. Mass                                          Spec.: MH.sup.+  = 430                    Preparative Example 52A                                                               ##STR603##                  m.p. = 77°-78° C. Mass                                          Spec.: MH.sup.+  = 444                    Preparative Example 52A                                                               ##STR604##                  m.p. = 78°-79° C. Mass                                          Spec.: MH.sup.+  = 444                    Preparative Example 49                                                                ##STR605##                  m.p. = 137°-138° C.                                             Mass Spec.: MH.sup.+  = 565               Preparative Example 1                                                                 ##STR606##                  Mass Spec.: MH.sup.+  = 451.2             Preparative Example 49                                                                ##STR607##                  Mass Spec.: MH.sup.+  = 531.2             Preparative Example 49A                                                               ##STR608##                  m.p. = 108.8°-109.7° C.                                         ass Spec.: MH.sup.+  = 465.4              Preparative Example 53                                                                ##STR609##                  Mass Spec.: MH.sup.+  = 475.2             Preparative Example 57                                                                ##STR610##                  m.p. = 151°-153° C.                                             Mass Spec.: MH.sup.+  = 560               Preparative Example 49A                                                               ##STR611##                  m.p. = 164.8°-165.2° C.                                         ass Spec.: MH.sup.+  = 546                Preparative Example 49A                                                               ##STR612##                  m.p. = 124.2°-125° C.                                           Mass Spec.: MH.sup.+  = 546               Preparative Example 49                                                                ##STR613##                  m.p. = 102.6°-103° C.                                           Mass Spec.: MH.sup.+  = 601.2             Preparative Example 73                                                                ##STR614##                  Mass Spec.: MH.sup.+  = 569               Preparative Example 49                                                                ##STR615##                  m.p. = 97° C. (dec.) Mass                                              Spec.: MH.sup.+  = 595                    Preparative Example 49                                                                ##STR616##                  m.p. = 132.6° C. (dec.) Mass                                           Spec.: MH.sup.+  = 576                    Preparative Example 49                                                                ##STR617##                  m.p. = 111.2° C. (dec.) Mass                                           Spec.: MH.sup.+  = 608                    Preparative Example 49                                                                ##STR618##                  m.p. = 85.1° C. (dec.) Mass                                            Spec.: MH.sup.+  = 556                    Preparative Example 49                                                                ##STR619##                  m.p. = 114° C. (dec.) Mass                                             Spec.: MH.sup.+  = 588                    Preparative Example 49                                                                ##STR620##                  m.p. = 122.5°-126.0° C.                                         dec.) Mass Spec.: MH.sup.+  =             __________________________________________________________________________                                        572                                   

EXAMPLE 411 ##STR621##

The product of Preparative Example 49 was reacted with2-methyl-2-(4-pyridyl)propanoic acid via substantially the sameprocedure as described for Example 180 to give the product compound.Mass Spec.: MH⁺ =538

Using the appropriate carboxylic acid (or carboxylate salt, e.g. lithiumcarboxylate) and the starting compound indicated, the followingcompounds were prepared via substantially the same procedure asdescribed for Example 410:

    __________________________________________________________________________    Starting                         Analytical                                   Compound                                                                             Product Compound          Data                                         __________________________________________________________________________    Preparative Example 49                                                                ##STR622##               Mass Spec.: MH.sup.+  = 554                         Example 411-A                                                          Preparative Example 53A                                                               ##STR623##               Mass Spec.: MH.sup.+  = 475.2                       Example 411-B                                                          Preparative Example 55                                                                ##STR624##               m.p. = 155.2°- 158.9° C.                                        Mass Spec.: MH.sup.+  = 446                         Example 411-C                                                          Preparative Example 49                                                                ##STR625##               Mass Spec.: MH.sup.+  = 554                         Example 411-D                                                          Preparative Example 1                                                                 ##STR626##               Mass Spec.: MH.sup.+  = 474                         Example 411-E                                                          Preparative Example 72                                                                ##STR627##               Mass Spec.: MH.sup.+  = 475                         Example 411-F                                                          Preparative Example 49                                                                ##STR628##               Mass Spec.: MH.sup.+  = 526.1                       Example 411-G                                                          Preparative Example 71                                                                ##STR629##               Mass Spec.: MH.sup.+  = 498                         Example 411-H                                                          Preparative Example 53B                                                               ##STR630##               Mass Spec.: MH.sup.+  = 589                         Example 411-J                                                          Preparative Example 53B                                                               ##STR631##               Mass Spec.: MH.sup.+  = 581                         Example 411-K                                                          Preparative Example 59                                                                ##STR632##               m.p. = 97°- 98° C. Mass                                         Spec.: (FAB) MH.sup.+  = 463.1                      Example 411-L                                                          Preparative Example 60                                                                ##STR633##               Mass Spec.: MH.sup.+  = 448                         Example 411-M                                                          Preparative Example 60                                                                ##STR634##               Mass Spec.: MH.sup.+  = 464                         Example 411-N                                                          Preparative Example 60                                                                ##STR635##               Mass Spec.: MH.sup.+  = 492                         Example 411-O                                                          Preparative Example 60                                                                ##STR636##               Mass Spec.: MH.sup.+  = 448                         Example 411-P                                                          Preparative Example 60                                                                ##STR637##               Mass Spec.: MH.sup.+  = 464                         Example 411-Q                                                          Preparative Example 60                                                                ##STR638##               Mass Spec.: MH.sup.+  = 469                         Example 411-R                                                          Preparative Example 60                                                                ##STR639##               Mass Spec.: MH.sup.+  = 469                         Example 411-S                                                          Preparative Example 60A                                                               ##STR640##               Mass Spec.: MH.sup.+  = 465                         Example 411-T                                                          Preparative Example 60A                                                               ##STR641##               Mass Spec.: MH.sup.+  = 481                         Example 411-U                                                          Preparative Example 60A                                                               ##STR642##               Mass Spec.: MH.sup.+  = 485                         Example 411-V                                                          Preparative Example 60A                                                               ##STR643##               Mass Spec.: MH.sup.+  = 481                         Example 411-W                                                          Preparative Example 60A                                                               ##STR644##               Mass Spec.: MH.sup.+  = 485                         Example 411-X                                                          Preparative Example 1 Step G                                                          ##STR645##               --                                                  Example 411-Z                                                          Preparative Example 51A                                                               ##STR646##               m.p. = 125°- 125.4° C.                                          Mass Spec.: MH.sup.+  = 528                         Example 411-AA                                                         Preparative Example 3 Step E                                                          ##STR647##               m.p. = 186.6°- 187° C.                                          Mass Spec.: MH.sup.+  = 464                         Example 411-BB                                                         Preparative Example 3 Step E                                                          ##STR648##               Mass Spec.: MH.sup.+  = 464                         Example 411-CC                                                         Preparative Example 51A                                                               ##STR649##               --                                                  Example 411-DD                                                         Preparative Example 49                                                                ##STR650##               m.p. = 83°- 86° C. Mass                                         Spec.: MH.sup.+  = 616                              Example 411-EE                                                         Preparative Example 49                                                                ##STR651##               m.p. = 167°- 171° C. Mass                                       Spec.: MH.sup.+  = 526                              Example 411-FF                                                         Preparative Example 49                                                                ##STR652##               m.p. = 134°- 140° C. Mass                                       Spec.: MH.sup.+  = 593                              Example 411-GG                                                         __________________________________________________________________________

EXAMPLE 412 ##STR653##

Combine 50 mg (0.11 mmol) of the compound of Example 400-N, and 1.5 mLof SOCl₂ and stir a room temperature overnight. Concentrate in vacuo toa residue, add 2.0 mL of DMF to the residue, then add 20 mg (0.2 mmol)of 1,2,4-triazole sodium salt and heat to 100° C. overnight. Cool themixture, concentrate in vacuo to remove most of the solvent, wash withwater (3 times), then dry the residue over Na₂ SO₄. Concentrate in vacuoto a residue and chromatograph (silica gel, 75% (10% NH₄ OH in MeOH) inCH₂ Cl₂) to give 26 mg of the product compound. Mass Spec.: MH⁺ =498

Using the appropriate starting compound and substantially the sameprocedure as described for Example 412, but substituting the aminenucleophile indicated in place of the 1,2,4-triazole sodium salt, thefollowing compounds were prepared:

    __________________________________________________________________________    Amine                            Analytical                                   Nucleophile                                                                           Product Compound         Data                                         __________________________________________________________________________    piperidine (solvent is CH.sub.2 Cl.sub.2 instead of DMF)                               ##STR654##              Mass Spec.: MH.sup.+  = 514.2                        Example 412-A                                                         thiomorpholine (solvent is CH.sub.2 Cl.sub.2 instead of                                ##STR655##              Mass Spec.: MH.sup.+  = 532.1                        Example 412-B                                                         piperazine (solvent is CH.sub.2 Cl.sub.2 instead of DMF)                               ##STR656##              Mass Spec.: MH.sup.+  = 515                          Example 412-C                                                         morpholine (solvent is CH.sub.2 Cl.sub.2 instead of DMF)                               ##STR657##              Mass Spec.: MH.sup.+  = 516.1                        Example 412-D                                                         imidazole (solvent is CH.sub.2 Cl.sub.2 instead of DMF)                                ##STR658##              Mass Spec.: MH.sup.+  = 497.2                        Example 412-E                                                         N-(2-methyl- phenyl)- piperazine (solvent is CH.sub.2 Cl.sub.2 instead of     DMF)                                                                                   ##STR659##              Mass Spec.: MH.sup.+  = 605.1                        Example 412-F                                                         4(3H)- pyrimidone                                                                      ##STR660##              Mass Spec.: MH.sup.+  = 525.1                        Example 412-G                                                         thiomorpholine                                                                         ##STR661##              m.p. = 105°- 105.6° C.                                          Mass Spec.: MH.sup.+  = 536                          Example 412-H                                                         thiomorpholine                                                                         ##STR662##              m.p. = 102.5°- 102.9° C.                                        Mass Spec.: MH.sup.+  = 550                          Example 412-J                                                         __________________________________________________________________________

EXAMPLE 413 ##STR663##

Combine 0.32 g of the product from Preparative Example 46 and 2 mL ofanhydrous CH₂ Cl₂ and add 6 mL of a mixture of 4.17 g ofN-methyl-4-piperidylacetic acid, 1.03 mL of methanesulfonyl chloride,6.83 mL of Et₃ N and 50 mL of CH₂ Cl₂. Stir at 25° C. overnight, thenadd 1N NaOH (aqueous) and shake well. Separate the layers, dry theorganic phase over MgSO₄, and concentrate to a residue. Chromatographthe residue (silica gel, 3% MeOH/CH₂ Cl₂ +NH₄ OH) to give 0.19 g (45%yield) of the product compound. m.p.=105° C. (dec); Mass Spec.: MH⁺=564.

EXAMPLE 414 ##STR664##

Combine 84 mg of the product from Preparative Example 46, 5 mL ofpyridine and 0.04 mL of phenylisocyanate and stir at 25° C. for 48hours. Concentrate in vacuo to a residue, dilute with CH₂ Cl₂ and washwith saturated NaHCO₃ (aqueous). Dry over MgSO₄, concentrate to sresidue and chromatograph (silica gel, 50-70% hexane/EtOAc) to give 14mg (13% yield) of the product compound. m.p.=125.6° C. (dec); MassSpec.: MH⁺ =544

Using the starting compound indicated, the following compounds wereprepared via substantially the same procedure as described for Example414:

    __________________________________________________________________________    Starting                     Analytical                                       Compound                                                                             Product Compound      Data                                             __________________________________________________________________________    Preparative Example 28                                                                ##STR665##           m.p. = 131.8° C. (dec.) Mass Spec.:                                    MH.sup.+  = 464                                         Example 414-A                                                          Preparative Example 53A                                                               ##STR666##           Mass Spec.: MH.sup.+  = 475.2                           Example 414-B                                                          __________________________________________________________________________

EXAMPLE 415 ##STR667##

Combine 0.64 g of the product from Example 411-C and 16 mL of glacialHOAc, and add 15 mL of a 0.54M solution of bromine in HOAc at 25° C.under N₂. After 10 minutes, pour the mixture into water, filter tocollect the resulting solid, and wash with water. Dry the solid undervacuum, then chromatograph (silica gel, 6-15% MeOH/CH₂ Cl₂) to give 0.26grams (35% yield) of the product compound. m.p.=150.0° C. (dec), MassSpec.: MH⁺ =526

EXAMPLE 416 ##STR668##

Combine 0.33 g of the product from Preparative Example 57, 2 mL ofanhydrous CH₂ Cl₂, and 10 mL of a mixture of 7.20 g of 4-pyridylaceticacid hydrochloride, 1.61 mL of methanesulfonylchloride, 27 mL of Et₃ Nand 60 mL of CH₂ Cl₂, and stir at 25° C. for 48 hours. Dilute themixture with CH₂ Cl₂, wash with saturated NaHCO₃ (aqueous), then withbrine. Dry over MgSO₄, concentrate to a residue and chromatograph(silica gel, 5% MeOH/CH₂ Cl₂ +NH₄ OH) to give 0.23 g (55% yield) of theproduct compound. m.p.=142° C. (dec); Mass Spec.: MH⁺ =540

EXAMPLE 417 ##STR669##

React the product from Preparative Example 35 with 4-pyridylacetic acidvia substantially the same procedure as described for Example 266 togive the product compound. Mass Spec.: MH⁺ =458

Using the appropriate carboxylic acid and the starting compoundindicated, the following compounds were prepared via substantially thesame procedure as described for Example 417:

    __________________________________________________________________________    Starting                     Analytical                                       Compound                                                                             Product Compound      Data                                             __________________________________________________________________________    Preparative Example 37B                                                               ##STR670##           Mass Spec.: MH.sup.+  = 444                             Example 417-A                                                          Preparative Example 58                                                                ##STR671##           Mass Spec.: MH.sup.+  = 522                             Example 417-B                                                          __________________________________________________________________________

EXAMPLE 418 ##STR672##

Follow the procedure of Example 283 except using 4-pyridylacetic acidN-oxide to give the product compound. Mass Spec.: MH⁺ =460

EXAMPLE 419 ##STR673##

Dissolve 4.01 g (8.42 mmol) of the compound of Example 410-L in EtOAcand add 14.25 g (63.1 mmol) of finely powdered SnCl₂ dihydrate and stirthe mixture for 5 hours. Add 150 mL of saturated NaF (aqueous) and stirfor 15 min, then separate the layers and dry the organic phase overMgSO₄. Filtration and concentrate in vacuo to a residue, thenchromatograph (silica gel, 95% CH₂ Cl₂ /MeOH+NH₄ OH) to give 2.95 g ofthe product compound. Mass Spec.: MH⁺ =461

EXAMPLE 420 ##STR674##

Combine 0.50 g (1.08 mmol) of the compound of Example 419 and 10 mL ofanhydrous CH₂ Cl₂, and add 0.11 mL (1.62 mmol) of CH₃ COCl. Add 0.34 mL(4.32 mmol) of pyridine and stir at room temperature for 2.5 hours.Dilute the mixture with saturated NaHCO₃ (aqueous), extract with CH₂Cl₂, wash the extracts with brine and dry over MgSO₄. Concentrate invacuo to a residue and chromatograph (silica gel, 10% MeOH/CH₂ Cl₂ +NH₄OH) to give 0.271 g of the product compound. Mass Spec.: MH⁺ =503

EXAMPLE 421 ##STR675##

Combine 0.65 g (1.41 mmol) of the product compound of Example 419, 20 mLof CH₂ Cl₂, 0.22 mL (3.52 mmol) of methyl iodide, 4.4 mL of 10% NaOH(aqueous) and 68 mg (0.21 mmol) of tetra-n-butyl-ammonium bromide. Stirthe mixture for 5 hours, then separate the layers and dry the organicphase over MgSO₄. Concentrate in vacuo to a residue and chromatograph(silica gel, 5% MeOH/CH₂ Cl₂ +NH₄ OH) to give 169 mg of the productcompound. Mass Spec.: MH⁺ =475

EXAMPLE 422 ##STR676##

Combine 0.1 g (0.21 mmol) of the product compound of Example 411-L and10 mL of CH₂ Cl₂, add 0.11 g (0.66 mmol) of MCPBA and stir at ambienttemperature for 1 hour. Wash with saturated NaHCO₃ (aqueous), dry overMgSO₄, and concentrate in vacuo to give 0.14 gm of the product compound.m.p.=100°-104° C.

Using the starting compound indicated, the following compounds wereprepared via substantially the same procedure as described for Example422:

    __________________________________________________________________________    Starting                    Analytical                                        Compound                                                                            Product Compound      Data                                              __________________________________________________________________________    Preparative Example 423                                                              ##STR677##           Mass Spec.: (FAB) MH.sup.+  = 480.2                     Example 422-A                                                           __________________________________________________________________________

EXAMPLE 423 ##STR678##

Combine 0.4 g (1.22 mmol) of the product compound of Preparative Example59 and 0.2 g (1.2 mmol) of 4-aminopyridylethylcarbamate and heat to 180°C. under a dry N₂ atmosphere for 2 hours. Cool the mixture andcrystallize the product by adding EtOAc to give 0.49 g of the productcompound. m.p.=206.4°-207° C.; Mass Spec.: (FAB) MH⁺ =464.0

Using the appropriate ethylcarbamate and the starting compoundindicated, the following compounds were prepared via substantially thesame procedure as described for Example 423:

    ______________________________________                                        Starting                        Analytical                                    Compound Product Compound       Data                                          ______________________________________                                        Preparative Example 1, Step G                                                           ##STR679##            --                                                     Example 423-A                                                        Preparative Example 1, Step G                                                           ##STR680##            --                                                     Example 423-B                                                        ______________________________________                                    

EXAMPLE 424 ##STR681##

Combine 1 g of the product of Example 402 and 20 mL of MeOH, cool to ˜0°C., and adjust to pH=3 by adding 1N HCl (aqueous). Add 1.25 mL of CH₃CHO and 1.41 g of NaCNBH₃, and stir the mixture for 1 hour. Concentratein vacuo to a residue, extract with 100 mL of CH₂ Cl₂ and wash theextract with 100 mL of 10% NaHCO₃, then with 100 mL of water. Dry overMgSO, concentrate in vacuo to a residue and chromatograph (silica gel,1.5% (10% NH₄ OH in MeOH)/CH₂ Cl₂) to give 0.158 g of the productcompound of Example 424 and 0.198 g of the product compound Example424-A.

Analytical data for Example 424: Mass Spec.: MH⁺ =474

Analytical data for Example 424-A: Mass Spec.: MH⁺ =502

EXAMPLE 425 ##STR682##

React the products of Preparative Example 7, Step C and PreparativeExample 26, via substantially the same procedure as described forExample 75 to give the title compound. Mass Spec.: MH⁺ =461.35

Using the appropriate carboxylic acid and the starting compoundindicated, the following compounds were prepared via substantially thesame procedure as described for Example 425:

    __________________________________________________________________________    Starting                    Analytical                                        Compound                                                                            Product Compound      Data                                              __________________________________________________________________________    Preparative Example 7                                                                ##STR683##           Mass Spec.: MH.sup.+  = 477.2                           Example 425-A                                                           Preparative Example 7                                                                ##STR684##           Mass Spec.: MH.sup.+  = 449.3                           Example 425-B                                                           Preparative Example 7                                                                ##STR685##           Mass Spec.: MH.sup.+  = 477.2                           Example 425-C                                                           Preparative Example 19 R(+)-isomer                                                   ##STR686##           Mass Spec.: MH.sup.+  = 449.2                           Example 425-D                                                           Preparative Example 19 S(-)-isomer                                                   ##STR687##           Mass Spec.: MH.sup.+  = 449.2                           Example 425-E                                                           Preparative Example 19 R(+)-isomer                                                   ##STR688##           Mass Spec.: MH.sup.+  = 449.3                           Example 425-F                                                           Preparative Example 19 S(-)-isomer                                                   ##STR689##           Mass Spec.: MH.sup.+  = 449.3                           Example 425-G                                                           Preparative Example 40                                                               ##STR690##           Mass Spec.: MH.sup.+  = 527.0                           Example 425-H                                                           Preparative Example 40                                                               ##STR691##           Mass Spec.: MH.sup.+  = 555.3                           Example 425-J                                                           Preparative Example 40                                                               ##STR692##           Mass Spec.: MH.sup.+  = 527.1                           Example 425-K                                                           Preparative Example 38                                                               ##STR693##           Mass Spec.: MH.sup.+  = 447.2                           Example 425-L                                                           Preparative Example 19 R(+)-isomer                                                   ##STR694##           Mass Spec.: MH.sup.+  = 453                             Example 425-M                                                           Preparative Example 19 S(-)-isomer                                                   ##STR695##           Mass Spec.: MH.sup.+  = 453                             Example 425-N                                                           Preparative Example 40                                                               ##STR696##           Mass Spec.: MH.sup.+  = 531.25                          Example 425-O                                                           Preparative Example 41                                                               ##STR697##           Mass Spec.: MH.sup.+  = 487.35                          Example 425-P                                                           Preparative Example 38                                                               ##STR698##           Mass Spec.: MH.sup.+  = 451.35                          Example 425-Q                                                           Preparative Example 19 R(+)-isomer                                                   ##STR699##           Mass Spec.: MH.sup.+  = 453.35                          Example 425-R                                                           Preparative Example 19 S(-)-isomer                                                   ##STR700##           Mass Spec.: MH.sup.+  = 453.35                          Example 425-S                                                           Preparative Example 7 Step C                                                         ##STR701##           Mass Spec.: MH.sup.+  = 539.45                          Example 425-T                                                           Preparative Example 40                                                               ##STR702##           Mass Spec.: MH.sup.+  = 531.35                          Example 425-U                                                           Preparative Example 38                                                               ##STR703##           Mass Spec.: MH.sup.+  = 451.4                           Example 425-V                                                           __________________________________________________________________________

EXAMPLE 426 ##STR704##

React the product of Preparative Example 40 and 3-pyridylacetic acid viasubstantially the same procedure as described for Example 351 to givethe title compound. Mass Spec.: MH⁺ =511

Using the appropriate carboxylic acid and the starting compoundindicated, the following compounds were prepared via substantially thesame procedure as described for Example 426:

    __________________________________________________________________________    Starting                    Analytical                                        Compound                                                                            Product Compound      Data                                              __________________________________________________________________________    Preparative Example 41                                                               ##STR705##           Mass Spec.: MH.sup.+  = 483.2                           Example 426-A                                                           __________________________________________________________________________

EXAMPLE 427 ##STR706##

Combine 0.288 g (1.76 mmol) of the product of Preparative Example 63 and25 mL of anhydrous toluene, heated at (110° C.) for 0.5 hours, then coolto 25° C. Add a solution of 0.1 g (0.293 mmol) of the productPreparative Example 7, Step C, in 1.5 mL of anhydrous toluene, and stirat 25° C. under an argon atmosphere for 112 hours. Concentrate in vacuoto a residue and chromatograph (silica gel, 3%-4% (10% NH₄ OH inMeOH)/CH₂ Cl₂) to give 0.065 g of the title compound. Mass Spec.: MH⁺=450.3

Using the appropriate azide and the starting compound indicated, thefollowing compounds were prepared via substantially the same procedureas described for Example 427:

    __________________________________________________________________________    Starting                    Analytical                                        Compound                                                                            Product Compound      Data                                              __________________________________________________________________________    Preparative Example 7, Step C                                                        ##STR707##           Mass Spec.: MH.sup.+  = 450.1                           Example 427-A                                                           Preparative Example 40                                                               ##STR708##           Mass Spec.: MH.sup.+  = 528.1                           Example 427-B                                                           Preparative Example 40                                                               ##STR709##           Mass Spec.: MH.sup.+  = 528.1                           Example 427-C                                                           __________________________________________________________________________

EXAMPLE 428 ##STR710##

Combine 14.73 g (27.3 mmol) of the compound from Example 193 and 125 mLof anhydrous MeOH, and add (in portions) 300 mL of a 10% solution ofconcentrated H₂ SO₄ in dioxane. Stir the mixture at 25° C. for 2 hours,then pour into water and adjust to pH=13 with 50% NaOH (aqueous).Extract with CH₂ Cl₂, wash the extract with water and dry over MgSO₄.Concentrate in vacuo to a residue and chromatograph (silica gel, 10%(10% NH₄ OH in MeOH)/CH₂ Cl₂) to give 8.9 g of the title compound. MassSpec.: MH⁺ =539

Using the starting compound indicated, the following compounds wereprepared via substantially the same procedure as described for Example428:

    ______________________________________                                        Starting                     Analytical                                       Compound                                                                              Product Compound     Data                                             ______________________________________                                        Example 425-T                                                                          ##STR711##          Mass Spec.: MH.sup.+  = 439.45                           Example 428-A                                                         ______________________________________                                    

EXAMPLE 429 ##STR712##

Combine 0.5 g (1.14 mmol) of the compound of Example 428 and 10 mL of0.6N HCl in CH₂ Cl₂, stir for 10 minutes and concentrate n vacuo to aresidue. Add 20 mL of anhydrous MeOH, then add 0.2006 g (4.56 mmol) ofCH₃ CHO, 0.0859 g (1.36 mmol) NaCNBH₃ and 0.5 g of 3A molecular sieves,and heat at 40° C. for 115 hours. Filter the mixture, wash the sieveswith MeOH and concentrate the combined filtrates in vacuo to a residue.Dissolve the residue in CH₂ Cl₂ and wash with saturated NaHCO₃(aqueous), then water and dry over MgSO₄. Concentrate in vacuo to aresidue and chromatograph (silica gel, 8% (10% NH₄ OH in MeOH)/CH₂ Cl₂)to give the title compound. Mass Spec.: MH⁺ =467.3

EXAMPLE 430 ##STR713##

Combine 0.5 g (1.14 mmol) of the compound of Example 428 and 5 mL ofanhydrous THF, add 0.1076 g (1.14 mmol) ClCO₂ CH₃, and stir at 25° C.for 1 hour. Concentrate in vacuo to a residue, add CH₂ Cl₂ and wash withsaturated NaHCO₃ (aqueous), then water. Dry the organic phase overMgSO₄, concentrate in vacuo to a residue and chromatograph (silica gel,1.5% (10% NH₄ OH in MeOH)/CH₂ Cl₂) to give 0.4213 g of the titlecompound. Mass Spec.: MH⁺ =497.35

Using the starting compound indicated, the following compounds wereprepared via substantially the same procedure as described for Example430:

    __________________________________________________________________________    Starting                    Analytical                                        Compound                                                                              Product Compound    Data                                              __________________________________________________________________________    Example 428-A                                                                         ##STR714##          Mass Spec.: MH.sup.+  = 497.35                           Example 430-A                                                          __________________________________________________________________________

EXAMPLE 431 ##STR715##

Combine 0.5 g (1.14 mmol) of the compound of Example 428 and 5 mL ofanhydrous CH₂ Cl₂, add 0.2624 g (2.28 mmol) of trimethylsilylisocyanateand stir under argon at 25° C. for 22 hours. Add 0.1312 g (1.14 mmol) oftrimethylsilylisocyanate and stir for 8 hours, then dilute with CH₂ Cl₂and wash with saturated NaHCO₃ (aqueous), then water. Dry over MgSO₄,concentrate in vacuo to a residue and chromatograph (silica gel, 5% (10%NH₄ OH in MeOH)/CH₂ Cl₂) to give 0.3878 g of the title compound. MassSpec.: MH⁺ =482.2

Using the isocyanate (or isothiocyanate) and starting compoundindicated, the following compounds were prepared via substantially thesame procedure as described for Example 431:

    __________________________________________________________________________    Starting                          Analytical                                  Compound                                                                              Product Compound          Data                                        __________________________________________________________________________    CH.sub.3 NCO Example 428                                                               ##STR716##               Mass Spec.: MH.sup.+  = 496.45                      Example 431-A                                                         CH.sub.3 CH.sub.2 NCO Example 428                                                      ##STR717##               Mass Spec.: MH.sup.+  = 510.35                      Example 431-B                                                         CH.sub.3 (CH.sub.2).sub.2 NCO Example 428                                              ##STR718##               Mass Spec.: MH.sup.+  = 524.35                      Example 431-C                                                         (CH.sub.3).sub.3 CNCO Example 428                                                      ##STR719##               Mass Spec.: MH.sup.+  = 538.35                      Example 431-D                                                         CH.sub.3 NCS and Example 428                                                           ##STR720##               Mass Spec.: MH.sup.+  = 512.25                      Example 431-E                                                         (CH.sub.3).sub.3 SiNCO Example 428-A                                                   ##STR721##               Mass Spec.: MH.sup.+  = 482.3                       Example 431-F                                                         CH.sub.3 NCO Example 428-A                                                             ##STR722##               Mass Spec.: MH.sup.+  = 496.35                      Example 431-G                                                         __________________________________________________________________________

EXAMPLE 432 ##STR723##

Combine 0.5 g (1.6 mmol) of the compound of Preparative Example 7 and1.098 g (6.4 mmol) of the compound from Preparative Example 65 and heatin a sealed vessel at 160° C. for 17 hours. Cool the mixture, add CH₂Cl₂, wash with water and dry the organic phase over MgSO₄. Concentratein vacuo to a residue and chromatograph (silica gel, 1.5% (10% NH₄ OH inMeOH)/CH₂ Cl₂) to give 0.0364 g of the title compound. Mass Spec.: MH⁺=454.25

EXAMPLE 433 ##STR724## Step A: ##STR725##

React 0.5 g (1.59 mmol) of the compound of Example 428 and 0.3232 g(2.39 mmol) of N-(tert-butoxycarbonyl)-L-alanine (0.3232 grams) (2.39mmoles) via essentially the same conditions as described in Example 425to give the product compound.

Step B: ##STR726##

Combine the product of Step A, 5 mL of MeOH and 10 mL of 10%concentrated H₂ SO₄ in dioxane and stir at 25° C. for 2 hours.Neutralize with Biorad AG1X8 (OH⁻) ion exchange resin, filter, wash theresin with 1:1 MeOH/water and concentrate the filtrate to a residue.Chromatograph the residue (silica gel, 8% (10% NH₄ OH in MeOH)/CH₂ Cl₂)to give the title compound. Mass Spec.: MH⁺ =510.35

Using the appropriate BOC-amino acid and the starting compoundindicated, the following compounds were prepared via substantially thesame procedure as described for Example 433:

    __________________________________________________________________________    Starting                       Analytical                                     Compound                                                                             Product Compound        Data                                           __________________________________________________________________________    BOC-L-serine and Example 428                                                          ##STR727##             Mass Spec.: MH.sup.+  = 526.2                         Example 433-A                                                          BOC-L- methionine and Example 428                                                     ##STR728##             Mass Spec.: MH.sup.+  = 570.3                         Example 433-B                                                          BOC-glycine and Example 428                                                           ##STR729##             Mass Spec.: MH.sup.+  = 496.35                        Example 433-C                                                          __________________________________________________________________________

EXAMPLE 434 ##STR730##

React the product of Preparative Example 67 with 4-pyridylacetic acidvia essentially the same procedure as described for Example 411 to givethe title compound. Mass Spec.: MH⁺ =410

Using the appropriate carboxylic acid and the starting compoundindicated, the following compounds were prepared via substantially thesame procedure as described for Example 434:

    __________________________________________________________________________    Starting                    Analytical                                        Compound                                                                            Product Compound      Data                                              __________________________________________________________________________    Preparative Example 68                                                               ##STR731##           mp.p = 68.6°- 70.3° C. Mass                                     Spec.: MH.sup.+  = 454                                  Example 434-A                                                           __________________________________________________________________________

EXAMPLE 435 ##STR732##

Dissolve 3.04 g (6.7 mmol) of the compound of Example 434-A in 100 mL ofMeOH. Add 100 mL of a 12% KOH (aqueous) and stir for one hour at 25° C.Remove the MeOH under vacuum, neutralize to pH 7 with 12N HCl andconcentrate in vacuo to a residue. Dry under vacuum and triturate with10 mL of EtOH, then filter, concentrate the filtrate in vacuo to givethe title compound. m.p.=238°-240° C.; Mass Spec.: MH⁺ =440

EXAMPLE 436 ##STR733##

Dissolve 0.5 g (1.14 mmol) of the product of Example 435 in 25 mL ofDMF, add 0.122 g (1.14 mmol) of benzylamine, 0.33 g (1.7 mmol) of DEC,0.15 g (1.1 mmol) of HOBT, and 0.23 g (2.27 mmol) of N-methylmorpholine,and stir at 25° C., under nitrogen for 18 hours. Concentrate in vacuo toa residue, add 20 mL of water and extract with 50 mL of EtOAc. Dry theorganic layer over MgSO₄ and concentrate in vacuo to a residue.Chromatograph (silica gel, 98% CH₂ Cl₂ /MeOH+NH₄ OH) to give the productcompound. m.p.=118°-120° C.; Mass Spec.: MH⁺ =529

Using the appropriate amine and the staring compound indicated, thefollowing compounds were prepared via substantially the same procedureas described for Example 436:

    __________________________________________________________________________    Starting                        Analytical                                    Compound                                                                            Product Compound          Data                                          __________________________________________________________________________    S-phenyl- alanine methyl ester and Example 435                                       ##STR734##               m.p. = 116.9° - 118.4° C.                                       Mass Spec.: MH.sup.+  = 622                         Example 436-A                                                           alanine and Example 435                                                              ##STR735##               m.p. = 137.8° - 139.9° C.                                       Mass Spec.: MH.sup.+  = 516                         Example 436-B                                                           ethanolamine and Example 435                                                         ##STR736##               m.p. = 130.9° - 132.5° C.                                       Mass Spec.: MH.sup.+  = 482                         Example 436-C                                                           NH.sub.4 Cl and Example 435                                                          ##STR737##               m.p. = 133.2° - 133.5° C.                                       Mass Spec.: MH.sup.+  = 439                         Example 436-D                                                           __________________________________________________________________________

EXAMPLE 437 ##STR738##

Dissolve 0.18 g (0.41 mmol) of the product of Example 435 in 2 mL oftoluene, add 0.12 g (0.43 mmol) of diphenylphosphoryl azide, 0.041 g(0.41 mmol) of Et₃ N, and 0.092 g (0.44 mmol) of benzyl alcohol and heatat reflux under nitrogen for 18 hours. Concentrate in vacuo to a residueand chromatograph (silica gel 95% CH₂ Cl₂ /MeOH) to obtain the titlecompound. m.p.=132.8°-133.7° C.; MH⁺ =545

EXAMPLE 438 ##STR739##

React the product of Preparative Example 70 with 4-pyridylacetic acidvia essentially the same procedure as described for Example 411 to givethe title compound. Mass Spec.: (FAB) MH⁺ =456

Using the appropriate carboxylic acid and the starting compoundindicated, the following compounds were prepared via substantially thesame procedure as described for Example 438:

    __________________________________________________________________________    Starting                      Analytical                                      Compound                                                                            Product Compound        Data                                            __________________________________________________________________________    Preparative Example 70                                                               ##STR740##             Mass Spec.: (FAB) MH.sup.+  = 476                     Example 438-A                                                           Preparative Example 70                                                               ##STR741##             Mass Spec.: (FAB) MH.sup.+  = 472                     Example 439-B                                                           __________________________________________________________________________

EXAMPLE 439 ##STR742##

Combine 1.7 g (5 mmol) of the product of Preparative Example 70, Step D,and 10 mL of anhydrous pyridine at 0° C. under N₂ atmosphere, thenslowly add (dropwise) 1 mL (7 mmol) of TFAA and stir at 25° C.overnight, Dilute with 100 ml of cold water, extract with CH₂ Cl₂ (2×75mL), wash the extracts successfully with 10% CuSO₄ (aqueous) and brine,then dry over MgSO₄. Concentrate in vacuo to a residue and chromatograph(silica gel 30%40% EtOAc/hexane) to give 1.75 g of the title compound.Mass Spec.: (FAB) MH⁺ =433

EXAMPLE 440 ##STR743##

Combine 0.07 g (0.154 mmol) of the product of Example 438, 7 mL of EtOHand 12 mg of PtO₂, and hydrogenate at 25° C. and atmospheric pressurefor 1 hour. Filter, wash with EtOH and concentrate in vacuo to give0.066 g of the title compound. Mass Spec.: (FAB) MH⁺ =458

Using the starting compound indicated, the following compounds wereprepared via substantially the same procedure as described for Example440:

    __________________________________________________________________________    Starting                       Analytical                                     Compound                                                                              Product Compound       Data                                           __________________________________________________________________________    Example 438-B                                                                          ##STR744##            Mass Spec.: (FAB) MH.sup.+  = 474                      Example 440-A                                                         __________________________________________________________________________

EXAMPLE 441 ##STR745##

Combine 0.07 g of the compound of Example 410-R, 2 mL of THF, 0.5 mL ofwater, 10 drops of glacial HOAc, and 0.1 g of powdered Zn, and stir themixture for 0.5 hours at 25° C. Purify the mixture by preparative thinlayer chromatography (Prep TLC), (silica gel, 10% (10% NH₄ OH inMeOH)/CH₂ Cl₂), to give a total of 68 mg of the crude product. Purifyagain by Prep TLC), (silica gel, 13% (10% NH₄ OH in MeOH)/CH₂ Cl₂), togive 33 mg of the product compound. Mass Spec.: MH⁺ =555

ASSAYS

1. In vitro enzyme assays: Inhibition of farnesyl protein transferaseand geranylgeranyl protein transferase.

Both farnesyl protein transferase (FPT) and geranylgeranyl proteintransferase (GGPT) I were partially purified from rat brain by ammoniumsulfate fractionation followed by Q-Sepharose (Pharmacia, Inc.) anionexchange chromatography essentially as described by Yokoyama et al(Yokoyama, K., et al., (1991), A protein geranylgeranyltransferase frombovine brain: Implications for protein prenylation specificity, Proc.Natl. Acad. Sci U.S.A. 88: 5302-5306, the disclosure of which isincorporated herein by reference thereto). Human farnesyl proteintransferase was also expressed in E. coli, using cDNA clones encodingboth the α and β subunits. The methods used were similar to thosepublished (Omer, C. et al., (1993), Characterization of recombinanthuman farnesyl protein transferase: Cloning, expression, farnesyldiphosphate binding, and functional homology with yeast prenyl-proteintransferases, Biochemistry 32:5167-5176). Human farnesyl proteintransferase was partially-purified from the soluble protein fraction ofE. coli as described above. The tricyclic farnesyl protein transferaseinhibitors disclosed herein inhibited both human and rat enzyme withsimilar potencies. Two forms of val¹² -Ha-Ras protein were prepared assubstrates for these enzymes, differing in their carboxy terminalsequence. One form terminated in cysteine-valine-leucine-serine(Ras-CVLS) the other in cystein-valine-leucine-leucine (Ras-CVLL).Ras-CVLS is a substrate for the farnesyl protein transferase whileRas-CVLL is a substrate for geranylgeranyl protein transferase I. ThecDNAs encoding these proteins were constructed so that the proteinscontain an amino-terminal extension of 6 histidine residues. Bothproteins were expressed in Escherichia coli and purified using metalchelate affinity chromatography. The radiolabelled isoprenylpyrophosphate substrates, ³ H!farnesyl pyrophosphate and ³H!geranylgeranyl pyrophosphate, were purchased from DuPont/New EnglandNuclear.

Several methods for measuring farnesyl protein transferase activity havebeen described (Reiss et al 1990, Cell 62: 81; Schaber et al 1990, J.Biol. Chem. 265: 14701; Manne et al 1990, PNAS 87: 7541; and Barbacid &Manne 1993, U.S. Pat. No. 5,185,248). The activity was assayed bymeasuring the transfer of ³ H!farnesyl from ³ H!farnesyl pyrophosphateto Ras-CVLS using conditions similar to those described by Reiss et al.1990 (Cell 62: 81) The reaction mixture contained 40 mM Hepes, pH 7.5;20 mM magnesium chloride; 5 mM dithiothreitol; 0.25 μM ³ H!farnesylpyrophosphate; 10 μl Q-Sepharose-purified farnesyl protein transferase;the indicated concentration of tricyclic compound or dimethylsulfoxide(DMSO) vehicle control (5% DMSO final); and 5 μM Ras-CVLS in a totalvolume of 100 μl. The reaction was allowed to proceed for 30 minutes atroom temperature and then stopped with 0.5 ml of 4% sodium dodecylsulfate (SDS) followed by 0.5 ml of cold 30% trichloracetic acid (TCA).Samples were allowed to sit on ice for 45 minutes and precipitated Rasprotein was then collected on GF/C filter paper mats using a Brandelcell harvester. Filter mats were washed once with 6% TCA, 2% SDS andradioactivity was measured in a Wallac 1204 Betaplate BS liquidscintillation counter. Percent inhibition was calculated relative to theDMSO vehicle control.

The geranylgeranyl protein transferase I assay was essentially identicalto the farnesyl protein transferase assay described above, with twoexceptions: ³ H!geranylgeranylpyrophosphate replaced farnesylpyrophosphate as the isoprenoid donor and Ras-CVLL was the proteinacceptor. This is similar to the assay reported by Casey et al (Casey,P. J., et al., (1991), Enzymatic modification of proteins with ageranylgeranyl isoprenoid, Proc. Natl. Acad. Sci, U.S.A. 88: 8631-8635,the disclosure of which is incorporated herein by reference thereto).

2. Cell-Based Assay: Transient expression of val¹² -Ha-Ras-CVLS andval¹² -Ha-Ras-CVLL in COS monkey kidney cells: Effect of farnesylprotein transferase inhibitors on Ras processing and on disordered cellgrowth induced by transforming Ras.

COS monkey kidney cells were transfected by electroporation with theplasmid pSV-SPORT (Gibco/BRL) containing a cDNA insert encoding eitherRas-CVLS or Ras-CVLL, leading to transient overexpression of a Rassubstrate for either farnesyl protein transferase or geranylgeranylprotein transferase I, respectively (see above).

Following electroporation, cells were plated into 6-well tissue culturedishes containing 1.5 ml of Dulbecco's-modified Eagle's media (GIBCO,Inc.) supplemented with 10% fetal calf serum and the appropriatefarnesyl protein transferase inhibitors. After 24 hours, media wasremoved and fresh media containing the appropriate drugs was re-added.

48 hours after electroporation cells were examined under the microscopeto monitor disordered cell growth induced by transforming Ras. Cellsexpressing transforming Ras become more rounded and refractile andovergrow the monolayer, reminiscent of the transformed phenotype. Cellswere then photographed, washed twice with 1 ml of coldphosphate-buffered saline (PBS) and removed from the dish by scrapingwith a rubber policeman into 1 ml of a buffer containing 25 mM Tris, pH8.0; 1 mM ethylenediamine tetraacetic acid; 1 mM phenylmethylsulfonylfluoride; 50 μM leupeptin; and 0.1 μM pepstatin. Cells were lysed byhomogenization and cell debris was removed by centrifugation at 2000×gfor 10 min.

Cellular protein was precipitated by addition of ice-coldtrichloroacetic acid and redissolved in 100 μl of SDS-electrophoresissample buffer. Samples (5-10 μl) were loaded onto 14% polyacrylamideminigels (Novex, Inc.) and electrophoresed until the tracking dye nearedthe bottom of the gel. Proteins resolved on the gels were electroblottedonto nitrocellulose membranes for immunodetection.

Membranes were blocked by incubation overnight at 4° C. in PBScontaining 2.5% dried milk and 0.5% Tween-20 and then incubated with aRas-specific monoclonal antibody, Y13-259 (Furth, M. E., et al., (1982),Monoclonal antibodies to the p21 products of the transforming gene ofHarvey murine sarcome virus and of the cellular ras gene family, J.Virol. 43: 294-304), in PBS containing 1% fetal calf serum for one hourat room temperature. After washing, membranes were incubated for onehour at room temperature with a 1:5000 dilution of secondary antibody,rabbit anti-rat IgG conjugated to horseradish peroxidase, in PBScontaining 1% fetal calf serum. The presence of processed andunprocessed Ras-CVLS or Ras-CVLL was detected using a colorimetricperoxidase reagent (4-chloro-1-naphthol) as described by themanufacturer (Bio-Rad).

3. Cell Mat Assay:

Normal human HEPM fibroblasts were planted in 3.5 cm dishes at a densityof 5×10⁴ cells/dish in 2 ml growth medium, and incubated for 3-5 d toachieve confluence. Medium was aspirated from each dish and theindicator tumor cells, T24-BAG4 human bladder carcinoma cells expressingan activated H-ras gene, were planted on top of the fibroblast monolayerat a density of 2×10³ cells/dish in 2 ml growth medium, and allowed toattach overnight. Compound-induced colony inhibition was assayed byaddition of serial dilutions of compound directly to the growth medium24 h after tumor cell planting, and incubating cells for an additional14 d to allow colony formation. Assays were terminated by rinsingmonolayers twice with phosphate-buffered saline (PBS), fixing themonolayers with a 1% glutaraldehyde solution in PBS, then visualizingtumor cells by staining with X-Gal (Price, J., et al., Lineage analysisin the vertebrate nervous system by retrovirus-mediated gene transfer,Proc. Natl. Acad. Sci. 84, 156-160(1987)). In the colony inhibitionassay, compounds were evaluated on the basis of two IC₅₀ values: theconcentration of drug required to prevent the increase in tumor cellnumber by 50% (tIC₅₀) and the concentration of drug required to reducethe density of cells comprising the cell mat by 50% (mIC₅₀). Both IC₅₀values were obtained by determining the density of tumor cells and matcells by visual inspection and enumeration of cells per colony and thenumber of colonies under the microscope. The therapeutic index of thecompound was quantitatively expressed as the ratio of mIC₅₀ /tIC₅₀, withvalues greater than one indicative of tumor target specificity.

RESULTS OF ASSAYS--TABLES 7 TO 28

The compounds listed in Table 7 refer to compounds of Formula 500.00:##STR746##

                  TABLE 7                                                         ______________________________________                                        EXAMPLE R                     FPT IC.sub.50 (μM)                           ______________________________________                                         1                                                                                                          0.25                                             2                                                                                     ##STR747##           0.47                                             3                                                                                     ##STR748##           0.66                                            88                                                                                     ##STR749##           1.0                                              4                                                                                     ##STR750##           1.0 0.8                                         53                                                                                     ##STR751##           1.5                                              5                                                                                     ##STR752##           1.7                                             89                                                                                     ##STR753##           1.8                                              6                                                                                     ##STR754##           2.0                                              7                                                                                     ##STR755##           2.3                                              8                                                                                     ##STR756##           2.3                                             90                                                                                     ##STR757##           3.4                                             91                                                                                     ##STR758##           3.9                                             92                                                                                     ##STR759##           3.9                                             93                                                                                     ##STR760##           3.9                                             94                                                                                     ##STR761##           4.0                                              9                                                                                     ##STR762##           4.0                                             95                                                                                     ##STR763##           4.2                                             10                                                                                     ##STR764##           4.3                                             11                                                                                     ##STR765##           4.3                                             12                                                                                     ##STR766##           4.3                                             96                                                                                     ##STR767##           4.3                                             97                                                                                     ##STR768##           4.4                                             98                                                                                     ##STR769##           4.4                                             99                                                                                     ##STR770##           4.4                                             13                                                                                     ##STR771##           4.5                                             100                                                                                    ##STR772##           4.5                                             101                                                                                    ##STR773##           4.6                                             102                                                                                    ##STR774##           4.6                                             14                                                                                     ##STR775##           4.6                                             103                                                                                    ##STR776##           4.6                                             104                                                                                    ##STR777##           4.7                                             15                                                                                     ##STR778##           4.7                                             16                                                                                     ##STR779##           4.8                                             17                                                                                     ##STR780##           4.8                                             52                                                                                     ##STR781##           4.9                                             18                                                                                     ##STR782##           4.9                                             105                                                                                    ##STR783##           5.0                                              .sup. 19A                                                                             ##STR784##           5.1                                             20                                                                                     ##STR785##           5.2                                             54                                                                                     ##STR786##           5.3                                             106                                                                                    ##STR787##           5.3                                             21                                                                                     ##STR788##           5.9                                             55                                                                                     ##STR789##           5.9                                             22                                                                                     ##STR790##           6.0                                             23                                                                                     ##STR791##           6.0                                             24                                                                                     ##STR792##           6.2                                             25                                                                                     ##STR793##           6.25                                            26                                                                                     ##STR794##           6.3                                             108                                                                                    ##STR795##           6.9                                             109                                                                                    ##STR796##           7.2                                             27                                                                                     ##STR797##           7.3                                             28                                                                                     ##STR798##           7.3                                             56                                                                                     ##STR799##           7.9                                             29                                                                                     ##STR800##           8.0                                             30                                                                                     ##STR801##           5.7                                             31                                                                                     ##STR802##           8.3                                             110                                                                                    ##STR803##           8.3                                             111                                                                                    ##STR804##           8.5                                             32                                                                                     ##STR805##           8.7                                             33                                                                                     ##STR806##           8.7                                             112                                                                                    ##STR807##           8.8                                             34                                                                                     ##STR808##           9.8                                             57                                                                                     ##STR809##           9.8                                             35                                                                                     ##STR810##           9.9                                             113                                                                                    ##STR811##           10.3                                            114                                                                                    ##STR812##           11.1                                            36                                                                                     ##STR813##           11.2                                            37                                                                                     ##STR814##           11.4                                            38                                                                                     ##STR815##           12.1                                            39                                                                                     ##STR816##           13.4                                            115                                                                                    ##STR817##           14.2                                            58                                                                                     ##STR818##           14.4                                            116                                                                                    ##STR819##           15.7                                            117                                                                                    ##STR820##           16.2                                            118                                                                                    ##STR821##           22.3                                            59                                                                                     ##STR822##           26.9                                            119                                                                                    ##STR823##           41% at 11 μM                                 120                                                                                    ##STR824##           4% at 39 μM                                  121                                                                                    ##STR825##           1.4                                             40                                                                                     ##STR826##           44% at 13 μM                                 122                                                                                    ##STR827##           23% at 12.5 μM                               123                                                                                    ##STR828##           23% at 12.6 μM                               124                                                                                    ##STR829##           37% at 12.8 μM                               125                                                                                    ##STR830##           10.3                                            126                                                                                    ##STR831##           2.9                                             127                                                                                    ##STR832##           3.5 2.7                                         128                                                                                    ##STR833##           3.0                                             129                                                                                    ##STR834##           32% at 11.8 μM                               41                                                                                     ##STR835##           6.1                                             42                                                                                     ##STR836##           0.6                                             43                                                                                     ##STR837##           0.6                                             44                                                                                     ##STR838##           0.8                                             45                                                                                     ##STR839##           1.2 0.87                                        46                                                                                     ##STR840##           1.2                                             47                                                                                     ##STR841##           1.3 1.01                                        48                                                                                     ##STR842##           1.3                                             49                                                                                     ##STR843##           1.4                                             84                                                                                     ##STR844##           0.29                                            83                                                                                     ##STR845##           0.59                                            19                                                                                     ##STR846##           1.0                                             85                                                                                     ##STR847##           2.0                                             219                                                                                    ##STR848##           6.64                                            220                                                                                    ##STR849##           2.49                                            221                                                                                    ##STR850##           3.71                                            222                                                                                    ##STR851##           0.38                                            227                                                                                    ##STR852##           0.53                                            228                                                                                    ##STR853##           7.5                                             287                                                                                    ##STR854##           0.72 5.02                                       288                                                                                    ##STR855##           1.11                                            289                                                                                    ##STR856##           1.44 1.4                                        290                                                                                    ##STR857##           3.8 2.55                                        291                                                                                    ##STR858##           0.87                                            292                                                                                    ##STR859##           0.99                                            293                                                                                    ##STR860##           1.76 0.47                                       294                                                                                    ##STR861##           2.11                                            295                                                                                    ##STR862##           2.4                                             296                                                                                    ##STR863##           4.1                                             297                                                                                    ##STR864##           2.71                                            298                                                                                    ##STR865##           4.58                                            299                                                                                    ##STR866##           1.34                                            300                                                                                    ##STR867##           0.96                                            ______________________________________                                    

The compounds listed in Table 8 refer to compounds of Formula 505.00:##STR868##

                                      TABLE 8                                     __________________________________________________________________________                                           FPT IC.sub.50                          EXAMPLE                                                                             A                     B          (μM)                                __________________________________________________________________________     .sup. 74B                                                                                                CH.sub.3   4.0                                     .sup. 74C                                                                           ##STR869##           CH.sub.3   11.6                                    .sup. 74A                                                                           ##STR870##           CH.sub.3   25% at 142 μM                       130                                                                                  ##STR871##           CH.sub.3   7% at 12.1 μM                       131                                                                                  ##STR872##                                                                                          ##STR873##                                                                              16% at 13.4 μM                       73                                                                                  ##STR874##           CH.sub.3   27% at 15.6 μM                      132                                                                                  ##STR875##           CH.sub.3   22% at 15 μM                        133                                                                                  ##STR876##           CH.sub.3   16% at 14.1 μM                      134                                                                                  ##STR877##                                                                                          ##STR878##                                                                              7% at 12.2 μM                       135                                                                                  ##STR879##           CH.sub.3   7.7                                     62                                                                                  ##STR880##           CH.sub.3   7.8                                     64                                                                                  ##STR881##           CH.sub.3   10.6                                   136                                                                                  ##STR882##           CH.sub.3   11.5                                    66                                                                                  ##STR883##           CH.sub.3   22% at 50 μM                        137                                                                                  ##STR884##           CH.sub.3   15% at 163 μM                        63                                                                                  ##STR885##           CH.sub.3   1% at 16.4 μM                       139                                                                                  ##STR886##           CH.sub.3   37% at 15.2 μM                      140                                                                                  ##STR887##           CH.sub.3   15.7                                    .sup. 71A                                                                           ##STR888##           CH.sub.3   17.6                                   141                                                                                  ##STR889##           CH.sub.3   29% at 50 μM                        143                                                                                  ##STR890##           CH.sub.3   35.4                                    .sup. 71B                                                                           ##STR891##           CH.sub.3   56.0                                   144                                                                                  ##STR892##           CH.sub.3   30% at 50 μM                         144a                                                                                ##STR893##                                                                                          ##STR894##                                                                              47% at 46 μM                         .sup. 71C                                                                           ##STR895##           CH.sub.3   38% at 15.5 μM                      145                                                                                  ##STR896##                                                                                          ##STR897##                                                                              >10                                    146                                                                                  ##STR898##                                                                                          ##STR899##                                                                              45% at 12 μM                        147                                                                                  ##STR900##           CH.sub.3   0% at 18.8 μM                       301                                                                                  ##STR901##                                                                                          ##STR902##                                                                              0.04 0.075                             180                                                                                  ##STR903##                                                                                          ##STR904##                                                                              0.072 0.04                             303                                                                                  ##STR905##                                                                                          ##STR906##                                                                              0.55                                   304                                                                                  ##STR907##                                                                                          ##STR908##                                                                              2.63                                   305                                                                                  ##STR909##                                                                                          ##STR910##                                                                              40% @ 4 μM                          230                                                                                  ##STR911##                                                                                          ##STR912##                                                                              2.06                                   307                                                                                  ##STR913##                                                                                          ##STR914##                                                                              0.22 0.14                              235                                                                                  ##STR915##                                                                                          ##STR916##                                                                              3.57                                   309                                                                                  ##STR917##                                                                                          ##STR918##                                                                              0.93                                   310                                                                                  ##STR919##                                                                                          ##STR920##                                                                              3.6                                    311                                                                                  ##STR921##                                                                                          ##STR922##                                                                              0.61                                   323                                                                                  ##STR923##                                                                                          ##STR924##                                                                              4.9                                    5.39                                                                                 ##STR925##                                                                                          ##STR926##                                                                              2.3                                    358                                                                                  ##STR927##                                                                                          ##STR928##                                                                              0.57                                   360                                                                                  ##STR929##                                                                                          ##STR930##                                                                              0.59                                   361                                                                                  ##STR931##                                                                                          ##STR932##                                                                              0.32                                   362                                                                                  ##STR933##                                                                                          ##STR934##                                                                              1.16                                   365                                                                                  ##STR935##                                                                                          ##STR936##                                                                              5.0                                    366                                                                                  ##STR937##                                                                                          ##STR938##                                                                              4.0                                    367                                                                                  ##STR939##                                                                                          ##STR940##                                                                              3.3                                    __________________________________________________________________________

Table 9 lists FPT IC₅₀ results for additional compounds.

                  TABLE 9                                                         ______________________________________                                                FPT                                                                           IC.sub.50        FPT IC.sub.50  FPT IC.sub.50                         EXAMPLE (μM)                                                                              EXAMPLE   (μM)                                                                              EXAMPLE (μM)                               ______________________________________                                        229     4.38   231       44% @  232     6.0                                   (5.104)        (5.106)   12 μM                                                                             (5.107)                                       236     1.48   237       18% @  238     26% @                                 (5.111)        (5.112)   4 μM                                                                              (5.113) 4 μM                               239     1.75   240       3.12   246     0.06                                  (5.114)        (5.115)          (5.121)                                       247     0.16   248       1.2    248     0.19                                  (5.122)        (5.124)          (5.123)                                       249     0.64   250       0.95   256     4.9                                   (5.125)        (5.126)          (5.132)                                       257     2.3    258       10.8   259     2.2                                   (5.133)        (5.134)          (5.135)                                       260     9.9    266       0.46   2.69    0.72                                  (5.136)        (5.138)          (5.140) 0.46                                  276     1.77   279       7.7    280     23                                    (5.145)        (5.147)          (5.148)                                       281     2.9    282       4.5    283     0.48                                  (5.149)        (5.150)          (5.151) 0.55                                  284     4.3    285       0.76   286     1.5                                   (5.152)        (5.153)          (5.154)                                       278     0.8    274       0.91   270     2.8                                                            1.38                                                 ______________________________________                                    

The compounds listed in Table 10 refer to compounds of Formula 510.00:##STR941##

                  TABLE 10                                                        ______________________________________                                        EXAMPLE R                     FPT IC.sub.50 (μM)                           ______________________________________                                        149                                                                                                         10.8                                            150                                                                                    ##STR942##           38% at 16.9 μM                               75                                                                                     ##STR943##           0.36 0.16                                       76                                                                                     ##STR944##           0.82                                            77                                                                                     ##STR945##           2.04                                            78                                                                                     ##STR946##           1.0 0.42                                        79                                                                                     ##STR947##           2.5                                             80                                                                                     ##STR948##           2.73                                            81                                                                                     ##STR949##           2.78                                            82                                                                                     ##STR950##           0.16 0.36                                       312                                                                                    ##STR951##           0.9                                             313                                                                                    ##STR952##           0.97                                            314                                                                                    ##STR953##           0.83                                            234                                                                                    ##STR954##           0.33                                            316                                                                                    ##STR955##           1.26                                            317                                                                                    ##STR956##           13.3                                            318                                                                                    ##STR957##           4.1                                             182                                                                                    ##STR958##           1.09                                            183                                                                                    ##STR959##           0.97 0.90                                       321                                                                                    ##STR960##           6                                               368                                                                                    ##STR961##           14 @ 12 μM                                   ______________________________________                                    

Table 11 lists FPT IC₅₀ results for additional compounds.

                  TABLE 11                                                        ______________________________________                                               FPT                                                                    EX-    IC.sub.50         FPT IC.sub.50  FPT IC.sub.50                         AMPLE  (μM) EXAMPLE   (μM)                                                                              EXAMPLE (μM)                               ______________________________________                                        187    1.34    187       0.95   188     4.6                                   (6.7)          (6.8)            (6.9)                                         189    2.44    190       3.3    191     4.9                                   (5.62)         (5.63)           (5.64)                                        192    1.24    194       4.3    195     6.8                                   (5.65)         (5.67)           (5.68)                                        196    0.36    197       1.17   198     0.85                                  (5.69)         (5.70)           (5.71)                                        199    10.8    199       10.2   200     0.87                                  (5.72A)        (5.72B)          (5.73)                                        201    1.4     202       20% @  203     11.3                                  (5.74)         (5.75)    11 μM                                                                             (5.76)                                        205    3.1     206       1.19   207     40% @                                 (5.78)         (5.79)           (5.80)  12 μM                              208    4.80    209       7.92   210     7.93                                  (5.81)         (5.82)           (5.83)                                        211    8.17    212       7.92   213     23% @                                 (5.84)         (5.85)           (5.86)  10 μM                              214    0% @    215       30% @  216     34% @                                 (5.87) 10 μM                                                                              (5.88)    13 μM                                                                             (5.89)  10 μM                              217    6.75    218       9.92   233     0.67                                  (5.90)         (5.91)           (5.108)                                       251    0.76    261       1.3    351     0.7                                   (5.127)                                                                              (6.12)                                                                 352    0.74    353       0.76   354     0.21                                  355    0.88    273                                                                           (5.143)          (6.17)                                        356    0.062   264       26% @  262     0.82                                         0.073   (6.15)    3.8 μM                                                                            (6.13)                                        263    9.8     253       4.3    350     2.1                                   (6.14)         (5.129)                                                        252    7.2     182       1.09   268     1.22                                  (5.128)        (6.4)            (5.139)                                       277    2.3     193       7.4    204     13.3                                  (6.20)                                                                        355    0.88    352       0.74   353     0.76                                                           0.38           0.30                                  ______________________________________                                    

The compounds listed in Table 12 refer to compounds of Formula 525.00:##STR962##

                                      TABLE 12                                    __________________________________________________________________________                                          FPT IC.sub.50                           EXAMPLE                                                                             A                B              (μM)                                 __________________________________________________________________________    184 (5.60)                                                                                            ##STR963##    0.91                                    185 (5.61)                                                                           ##STR964##                                                                                     ##STR965##    3.8                                     223 (5.96)                                                                           ##STR966##                                                                                     ##STR967##    2.1                                     223 (5.97)                                                                           ##STR968##                                                                                     ##STR969##    0.19 0.72 0.61                          224 (6.10)                                                                           ##STR970##                                                                                     ##STR971##    3.2                                     224 (6.11)                                                                           ##STR972##                                                                                     ##STR973##    0.46                                    225 (5.98)                                                                           ##STR974##                                                                                     ##STR975##    3.5                                     225 (5.99)                                                                           ##STR976##                                                                                     ##STR977##    1.6                                      226 (5.100)                                                                         ##STR978##                                                                                     ##STR979##    4.1                                      226 (5.101)                                                                         ##STR980##                                                                                     ##STR981##    1.8                                     351                                                                                  ##STR982##                                                                                     ##STR983##    0.17                                    354                                                                                  ##STR984##                                                                                     ##STR985##    0.21                                    __________________________________________________________________________

The compounds listed in Table 13 refer to compounds of Formula 515.00:##STR986##

                  TAB:E 13                                                        ______________________________________                                        EXAMPLE  R                   FPT IC.sub.50 (μM)                            ______________________________________                                        151                                                                                                        15.0                                             152                                                                                     ##STR987##         15.0                                             153                                                                                     ##STR988##         29.6                                             87                                                                                      ##STR989##         1.14                                             ______________________________________                                    

Additional FPT IC₅₀ results were: (1) Example 180, compound 5.47, 0.072μM; (2) Example 181, compound 5.48, 0.23 μM; (3) Example 182, compound6.4, 1.09 μM; and (4) Example 183, compound 6.5, 0.97 μM.

Tables 20-22 disclose FPT Inhibition data for additional compounds.

                  TABLE 20                                                        ______________________________________                                        EXAMPLE  FPT IC.sub.50 (μM)                                                                      EXAMPLE    FPT IC.sub.50 (μM)                        ______________________________________                                        400 (5.210)                                                                            0.068        401 (5.209)                                                                              0.063                                                                         0.08                                         400-B (5.203)                                                                          0.068        400-C (5.200)                                                                            0.030                                        400-D (5.217)                                                                          0.21         400-E (5.208)                                                                            0.04                                         400-F (5.201)                                                                          0.036        400-G (5.204)                                                                            0.024                                        400-H (5.220)                                                                          0.24         400-J (5.212)                                                                            0.14                                         400-K (5.218)                                                                          0.21         400-L (5.206)                                                                            0.095                                                                         0.09                                         ______________________________________                                    

                  TABLE 21                                                        ______________________________________                                        EXAMPLE  FPT IC.sub.50 (μM)                                                                      EXAMPLE    FPT IC.sub.50 (μM)                        ______________________________________                                        411      0.32         411-A      0.59                                         411-B    0.32         402-A      0.45                                                                          0.56                                         411-D    0.62         411-E      11.4                                         411-F    1.28         411-G      0.7                                          411-L    0.82         402        1.0                                          405      1.3          406        1.4                                          413      0.103        414-A      1.90                                         414      0.90         417        1.16                                         418      1.85         417-A      0.85                                         417-B    0.14         419        <0.12                                        420      0.23         422        0.60                                         423      >4.3         422-A      >1.2                                                  35 (4.3)                22 (1.2)                                     411-N    ˜2     411-M      0.65                                                  44 (1.3)                                                             411-R    ˜4     411-S      2.1                                                   29 (1.30)                                                            411-P    3.8          411-Q      ˜10                                                                     33 (4.3)                                     411-O    ˜5     411-X      0.45                                                  39 (4)                                                               411-V    0.27         411-T      0.58                                         411-W    0.16         411-U      1.12                                                  0.17                                                                 425      1.74         425-B      0.74                                         425-A    2.2          425-C      1.26                                         425-E    0.49         425-D      1.2                                          425-G    2.3          425-F      7                                            426 (5.207)                                                                            0.012        425-H (5.202)                                                                            0.059                                                                         0.059                                                                         0.049                                                                         0.075 bv                                     425-J    0.39         425-K      0.40                                                                          0.41                                         425-L    4.5          426-A      0.33                                         427      1.8          427-A      2.2                                          425-N    0.64         428        1.25                                         429      1.27         425-M      1.8                                          431      0.82         431-C      0.88                                         431-B    0.92         431-D      1.0                                          431-A    1.05         430        1.3                                          431-E    0.88         425-O (5.126)                                                                            0.17                                                                          0.14                                                                          0.122                                                                         0.118                                                                         0.178 bv                                     425-P    0.45         425-Q      1.37                                         425-S    0.6          425-R      1.7                                          428-A    1.1          431-F      1.75                                         430-A    7            431-G      7                                            425-T    12.2         425-U (5.211)                                                                            0.10                                                                          0.14                                         425-V    1.66         434        0.26                                                                          70 (0.48)                                    434-A    3.5          435        7.0                                          437      1000         411-Z      1.5                                                   36 (11)                                                              427-B    0.21         427-C      0.24                                         432      0.66         415        >3.8                                         411-C    6.0          400-M      0.9                                          411-DD   3.1          411-EE     10 (3.3)                                     411-FF   1.8                                                                  ______________________________________                                    

                  TABLE 22                                                        ______________________________________                                        EXAMPLE  FPT IC.sub.50 (μM)                                                                      EXAMPLE    FPT IC.sub.50 (μM)                        ______________________________________                                        410      0.70         410-A      0.086                                        410-B    0.084        410-C      0.052                                        410-D                 410-E      1000                                                                          31 (4.5)                                     410-F    2.2          410-G      0.21                                         410-H    7            410-J      1.9                                          412      0.52         410-L      2.9                                          403      1000         404        4.6                                                                15 (12)                                                 401-A    1.7          400-A      2.6                                          412      0.52         416        3.7                                          410-M    ˜12    424        1.3                                                   27 (3.6)                                                             424-A    1000         433        2.5                                                   22 (4)                                                               433-A    1.1          433-B      1.89                                         433-C    2.5          436        17                                           436-A    1000         436-B      1000                                                  17 (9.6)                2 (10.6)                                     436-C    1000         436-D      0.75                                                  36 (10)                                                              410-S    1000         410-T      1.8                                                   32 (3.4)                                                             410-U    5            410-V      1.17                                                  40 (3.3)                                                             410-W    1.16                                                                 ______________________________________                                    

                  TABLE 14                                                        ______________________________________                                        COMPARISON OF FPT INHIBITION AND GGPT INHIBITION                                       ENZYME INHIBITION                                                                            ENZYME INHIBITION                                     EXAMPLE  FPT IC.sub.50 μM                                                                          GGPT IC.sub.50 μM                                  ______________________________________                                        1        0.25           >46                                                   2        0.47           >46                                                   3        0.66           >39                                                   5        1.7            >46                                                   7        2.3            >45                                                   8        2.3             42                                                   181      0.23           >42                                                   78       2.19           >46                                                            0.53                                                                          0.74                                                                          0.76                                                                          0.97                                                                 77       2.04           >39                                                   79       2.5            >50                                                   76       0.82           >40                                                   ______________________________________                                    

                  TABLE 23                                                        ______________________________________                                        COMPARISON OF FPT INHIBITION AND GGPT INHIBITION                                       ENZYME INHIBITION                                                                            ENZYME INHIBITION                                     EXAMPLE  FPT IC.sub.50 μM                                                                          GGPT IC.sub.50 μM                                  ______________________________________                                        400-D    0.21           >38                                                   400-C    0.030          >38                                                   400-B    0.068          >38                                                   400-E    0.04           1000                                                                          30 (38)                                               400-F    0.036          1000                                                                          0 (36)                                                400-G    0.024          >39                                                   400-H    0.24           1000                                                                          0 (36)                                                400-J    0.14           1000                                                                          6 (36)                                                400-K    0.21           1000                                                                          6 (37)                                                400      0.068          1000                                                                          29 (36)                                               401      0.063          1000                                                           0.08           7 (34)                                                413      0.103          >35                                                   417-B    0.14           1000                                                                          15 (32)                                               419      <0.12          1000                                                                          0 (41)                                                411-W    0.16           1000                                                           0.17           3 (42)                                                426      0.012          >39                                                   425-H    0.059          >38                                                            0.059                                                                         0.049                                                                         0.075 bv                                                             425-O    0.17           >38                                                            0.14                                                                          0.122                                                                         0.118                                                                         0.178 bv                                                             425-U    0.10           >38                                                            0.14                                                                 400-L    0.095           38                                                            0.09                                                                 ______________________________________                                    

                  TABLE 24                                                        ______________________________________                                        COMPARISON OF FPT INHIBITION AND GGPT INHIBITION                                       ENZYME INHIBITION                                                                            ENZYME INHIBITION                                     EXAMPLE  FPT IC.sub.50 μM                                                                          GGPT IC.sub.50 μM                                  ______________________________________                                        410-G    0.21           1000                                                                          32 (33)                                               410-A    0.086          ˜40                                                                     47 (35)                                               410-B    0.084          1000                                                                          21 (35)                                               ______________________________________                                    

                  TABLE 15                                                        ______________________________________                                        ACTIVITY IN COS CELLS                                                                  Inhibition of Ras     Inhibition of Ras                                       Processing            Processing                                     Example  IC.sub.50 (μM)                                                                          Example  IC.sub.50 (μM)                              ______________________________________                                        1        1.0          --       --                                             82       1.2          156 (5.46)                                                                             2.7                                            75       3.7          2        3.7                                            45       4.2          157      4.5                                            78       <4.6         42       5.8                                            19       6.2          89.      6.3                                            83       7.4          5        9.2                                            77       9.2          43       9.7                                            6        10.0         49       10.7                                           47       11.1         44       11.6                                           87       12.7         46       >8.0                                           85       >37.4        84       >9.7                                           3        >10          76       39.9                                           154 (5.28)                                                                             >10.0        48       10.7                                           5        >12          88       >12                                            53       >13          181 (5.48)                                                                             1.1                                            278      2.6          274      8.0                                            ______________________________________                                    

In Table 15, the numbers in parenthesis in the Example column refer tothe formula number for the compound used in the indicated example. Also,the compound of Example 157 is: ##STR990##

                  TABLE 25                                                        ______________________________________                                        ACTIVITY IN COS CELLS                                                                  Inhibition of Ras     Inhibition of Ras                                       Processing            Processing                                     Example  IC.sub.50 (μM)                                                                          Example  IC.sub.50 (μM)                              ______________________________________                                        411      ˜1     411-A    0.7                                                     93 (5)                                                               411-B    1.8          441-D    1.6                                            400-D    2.0          400-C    0.7                                            402      >10          411-G    5.1                                            400-G    0.58         400-H    2.5                                                                           100 (5)                                        400-K    2.2          411-B    1.8                                                     100 (5)                                                              400-D    2.0          400-C    0.7                                            400-G    0.58         413      1.5                                            417      4.0          418      >10                                            425-E    5.0          426      0.38                                           425-H    0.63         425-J    5.0                                                     0.45                                                                 425-K    0.45         426-A    >5.0                                           425-O    0.10         425-P    5.7                                                     tox (10)                                                                      0.4                                                                  425-U    0.45         434      <<5                                                     tox (10)                                                             400-L    0.6                                                                           0.65                                                                 ______________________________________                                    

                  TABLE 26                                                        ______________________________________                                        ACTIVITY IN COS CELLS                                                                  Inhibition of Ras     Inhibition of Ras                                       Processing            Processing                                     Example  IC.sub.50 (μM)                                                                          Example  IC.sub.50 (μM)                              ______________________________________                                        410-G    4.0          410-D    18.5                                           ______________________________________                                    

                  TABLE 16                                                        ______________________________________                                        INHIBITION OF TUMOR CELL GROWTH                                               MAT ASSAY                                                                             Tumor   Normal            Tumor Normal                                        IC.sub.50                                                                             IC.sub.50         IC.sub.50                                                                           IC.sub.50                             Example (μM) (μM)   Example (μM)                                                                             (μM)                               ______________________________________                                        75      2.5     >50.0     --      --    --                                    1       3.1     25.0      82      3.1   40.0                                  5       6.3     >50.0     89      6.3   >25.0                                 127     6.3     >50.0     45      6.3   >50.0                                 88      8.0     >50.0     6       12.5  50.0                                  49      12.5    >50.0     47      12.5  >50.0                                 48      12.5    25.0      79      12.5  >50.0                                 158 (5.36)                                                                            12.5    18.0      2       25.0  >50.0                                 10      25.0    >50.0     128     25.0  >50.0                                 44      25.0    25.0      164 (5.30)                                                                            25.0  >50.0                                 43      25.0    50.0      165 (5.34)                                                                            25.0  50.0                                  53      25.0    >50.0     166 (5.26)                                                                            37.0  >50.0                                 159 (5.31)                                                                            37.0    >50.0     167 (5.32)                                                                            37.0  50.0                                  160 (5.39)                                                                            37.0    50.0      168 (5.44)                                                                            37.0  >50.0                                 161 (5.45)                                                                            37.0    >50.0     5       37.5  100.0                                 162 (5.29)                                                                            37.0    >50.0     93      40.0  >50.0                                 94      40.0    80.0      88      >50.0 >50.0                                 3       >50.0   >50.0     7       50.0  100.0                                 90      50.0    >50.0     91      50.0  80.0                                  95      >50.0   >50.0     11      >50.0 >50.0                                 12      50.0    >50.0     96      50.0  >50.0                                 97      >50.0   >50.0     98      50.0  >50.0                                 121     50.0    >50.0     126     50.0  >50.0                                 163 (5.27)                                                                            50.0    >50.0     42      50.0  >50.0                                 154 (5.28)                                                                            >50.0   >50.0     169 (5.33)                                                                            >50.0 >50.0                                 46      50.0    >50.0     80      >50.0 >50.0                                 77      >50.0   >50.0     76      >50.0 >50.0                                 81      >50.0   >50.0     173 (5.35)                                                                            >50.0 >50.0                                 170 (5.37)                                                                            50.0    >50.0     174 (5.38)                                                                            50.0  50.0                                  171 (5.40)                                                                            50.0    >50.0     87      50.0  >50.0                                 172 (5.42)                                                                            >50.0   >50.0     175 (5.43)                                                                            >50.0 >50.0                                 180 (5.47)                                                                            18      >50.0     181 (5.48)                                                                            <3.1  >50.0                                 ______________________________________                                    

In Table 16, the numbers in parenthesis in the Example column refer tothe formula number for the compound used in the indicated example.

                  TABLE 27                                                        ______________________________________                                        INHIBITION OF TUMOR CELL GROWTH                                               MAT ASSAY                                                                             Tumor   Normal            Tumor Normal                                        IC.sub.50                                                                             IC.sub.50         IC.sub.50                                                                           IC.sub.50                             Example (μM) (μM)   Example (μM)                                                                             (μM)                               ______________________________________                                        411-A   1.6     >25       411     18    >25                                   411-B   6.25    >25       402-A   3.1   >25                                   411-D   8       >25       411-E   >25   >25                                   400-D   4       >25       400-C   <1.6  >25                                   402     18      >25       400-B   <1.6  6.25                                  411-G   6.25    >25       400-E   <1.6  18                                            4       >12.5                                                         400-F   <1.6    >25       405     12.5  >25                                   400-G   1.6     >25       400     1.6   >25                                   401     <1.6    >25       411-B   6.25  >25                                   402-A   3.1     >25       400-D   4     >25                                   400-C   <1.6    >25       400-B   <1.6  >25                                   400-G   1.6     >25       413     >6.25 10                                    417     10      18        418     25    >25                                   417-B   <1.6    >25       425     12.5  >25                                   425-B   12.5    >25       425-E   1.6   >25                                   426     3.1     25        425-H   <1.6  >25                                           <0.8    >12.5                                                         425-J   3.1     >25       425-K   6.25  >25                                   426-A   6.25    >25       428     12.5  18                                    425-O   3.1     6.25      425-P   >3.1  3.1                                           <0.8    6.25                                                          425-U   6.25    10        400-L   <1.6  >25                                                                     <0.8  >12.5                                 ______________________________________                                    

                  TABLE 28                                                        ______________________________________                                        INHIBITION OF TUMOR CELL GROWTH                                               MAT ASSAY                                                                             Tumor   Normal            Tumor Normal                                        IC.sub.50                                                                             IC.sub.50         IC.sub.50                                                                           IC.sub.50                             Example (μM) (μM)   Example (μM)                                                                             (μM)                               ______________________________________                                        410-D   10      >50.0                                                         ______________________________________                                    

                  TABLE 17                                                        ______________________________________                                                       COS CELLS   Inhibition                                                        Activity    of Tumor Cell                                              Enzyme Inhibition of                                                                             Growth                                                     Inhibition                                                                           Ras         MAT Assay                                                  GGPT   Processing  IC.sub.50 (μM)                                  Example   IC.sub.50 (μM)                                                                      IC.sub.50 (μM)                                                                         Tumor Normal                                   ______________________________________                                        180       >42      1.0         18    >50                                                         6.3         12.5  50                                                          2.4         12.5  >50                                      182 (6.4) >40      12.0        37    >50                                      183 (6.5) >40      10.5        5     18                                       184 (5.60)                                                                              --       11.5        12.5  >50                                      185 (5.61)                                                                              --       >20         --    --                                       187 (6.7) >46      4.8         37    >50                                                                     25    >50                                      187 (6.8) >46      1.3         9     >50                                                                     4     50                                       189 (5.62)                                                                              42       7.0         37    >50                                      190 (5.63)                                                                              --       --          >50   >50                                      191 (5.64)                                                                              --       --          <3.1  50                                       192 (5.65)                                                                              >43      4.9         25    >50                                                                     37    >50                                      196 (5.69)                                                                              >46      5.0         37    >50                                                                     25    >50                                      197 (5.70)                                                                              --       11.1        25    >50                                      198 (5.7l)                                                                              --       6.1         12.5  >50                                      200 (5.73)                                                                              --       2.7         18    >50                                      201 (5.74)                                                                              --       0.93        31    12.5                                     206       --       2.4         <3.1  16                                       208 (5.81)                                                                              --       --          >50   >50                                      209 (5.82)                                                                              --       --          25    >50                                      211 (5.84)                                                                              --       --          37    >50                                      212 (5.85)                                                                              --       --          25    37                                       217 (5.90)                                                                              --       --          37    50                                       218 (5.91)                                                                              --       --          37    50                                       219 (5.92)                                                                              --       --          25    >50                                      220 (5.93)                                                                              --       --          25    >50                                      221 (5.94)                                                                              --       --          6.25  >50                                      222 (5.95)                                                                              --       4.7         18    37                                       223 (5.96)                                                                              --       10.5        25    >50                                      223 (5.97)                                                                              --       1.3         8     >50                                      224 (61.1)                                                                              --       7.3         37    >50                                      225 (5.98)                                                                              --       --          12.5  50                                       225 (5.99)                                                                              --       6.2         12.5  >50                                      226 (5.100)                                                                             --       --          25    >50                                      226 (5.101)                                                                             --       6.5         12.5  >50                                      227 (5.102)                                                                             >41      1.0         4     μ50                                   229 (5.104)                                                                             --       --          37    >50                                      230 (5.105)                                                                             --       >20         37    >50                                      233 (5.108)                                                                             --       10          18    >50                                      235       --       9.1         12.5  >50                                      236 (5.111)                                                                             >45      3.5         4     >50                                      237 (5.112)                                                                             --       --          >50   >50                                      238 (5.113)                                                                             --       --          >50   >50                                      239 (5.114)                                                                             --       4.6         37    >50                                      246 (5.121)                                                                             >40      μ3.9     12.5  50                                                          3.1         μ3.1                                                                             >50                                                         0.91                                                       247 (5.122)                                                                             >40      >3.9        25    >50                                                         3.5         8     >50                                      248 (5.124)                                                                             --       2.05        μ8 >50                                      248 (5.123)                                                                             --       4.6         18    >50                                      250 (5.126)                                                                             --       8.6         18    >50                                      251 (5.127)                                                                             --       8.1         --    --                                       261 (6.12)                                                                              --       9.1         --    --                                       266 (5.138)                                                                             --       0.77        3.1   6.25                                                        0.89                                                       267 (6.17)                                                                              --       12.5        --    --                                       269 (5.140)                                                                             --       0.69        6.25  12.5                                     276 (5.145)                                                                             --       2.9         12.5  50                                       281 (5.149)                                                                             --       7.0         4     >50                                      283 (5.151)                                                                             --       5.6         10    >50                                      285 (5.153)                                                                             --       5.2         12.5  >50                                                         10.1                                                       286 (5.154)                                                                             --       8.3         25    >50                                      287       >40      >10         3.1   >50                                                         >10         50    >50                                                                     25                                             288       --       2.8         8     >50                                      289       >40      >10         12.5  >50                                                                     18    >50                                                                     12.5  >50                                      290       >38      --          12.5  >50                                                                     6.25  >50                                                                     8     >50                                      291       >46      3.6         18    >50                                      292       >44      6.8         6.25  >50                                      293       >40      >11.1       12.5  >50                                                         6.5         12.5  >50                                                                     12.5  >50                                      294       --       5.2         18    >50                                                         2.8                                                        *295      --       20.8        --    --                                       297       41       --          >50   >50                                      298       >35      >9          >50   >50                                      299       1000     --          --    --                                       300       --       2.6         <3.1  >50                                      301       40       4.4         12.5  >50                                                         1.0         <3.1  >50                                                                     <3.1  >50                                      303       >43      3.4         8     >50                                      304       >40      --          50    >50                                      305       --       --          25    >50                                      307       --       4.6         12.5  50                                                          0.85                                                       309       35.1     >10         --    --                                       310       --       --          25    >50                                      311       41.3     9.5         10    >50                                      312       >46      3.8         12.5  >50                                      313       >46      1.5         6.25  >50                                      314       >46      3.0         4     >50                                      234       >43      2.2         3.1   >50                                      316       >43      18.4        25    >50                                      318       --       --          37    37                                       321       --       --          6.25  >50                                      322       --       2.8         8     >50                                      351       1000     2.8         6.25  25                                       354       1000     --          6.25  ≧25                               365       --       3.1         6.25  >50                                      366       --       3.3         3.1   >50                                      367       --       6.2         6.25  >50                                      78        >46      --          --    --                                       77        >39      --          --    --                                       79        >50      5.1         --    --                                       76        >50      --          --    --                                       350       --       3.7         --    --                                       355       --       0.89        8     >25                                      352       --       2.2         1.6   >25                                      353       --       0.9         6.25  >25                                      ______________________________________                                    

RESULTS:

1. Enzymology:

The data demonstrate that the compounds of the invention are inhibitorsof Ras-CVLS farnesylation by partially purified rat brain farnesylprotein transferase (FPT). The data also show that there are compoundsof the invention which can be considered as potent (IC₅₀ <10 μM)inhibitors of Ras-CVLS farnesylation by partially purified rat brainFPT.

The data also demonstrate that compounds of the invention are poorerinhibitors of geranylgeranyl protein transferase (GGPT) assayed usingRas-CVLL as isoprenoid acceptor. Generally, the compounds of theinvention are inactive or weakly active as geranylgeranyl transferaseinhibitors at 20 μg/mL. For example, with reference to Table 14, thecompound of Example 1 inhibits GGPT 24% at 46 μM and is at least184-fold selective for FPT inhibition. The compound of Example 2, forexample, inhibits GGPT 25% at 46 μM and is at least 98-fold selectivefor FPT inhibition. For another example, the compound of Example 3inhibits GPPT 3% at 39 μM and is at least 59-fold selective for FPT.This selectivity is important for the therapeutic potential of thecompounds used in the methods of this invention, and increases thepotential that the compounds will have selective growth inhibitoryproperties against Ras-transformed cells.

2. Cell-Based:

COS Cell Assay

Western blot analysis of the Ras protein expressed in Ras-transfectedCOS cells following treatment with the tricyclic farnesyl proteintransferase inhibitors of this invention indicated that they inhibitRas-CVLS processing, causing accumulation of unprocessed Ras (see Table15). The compound of Example 1, for example, inhibited Ras-CVLSprocessing with an IC₅₀ value of 1 μM (0.44 μg/mL), but did not blockthe geranylgeranylation of Ras-CVLL at concentrations up to 20 μg/mL.Microscopic and photographic examination of the Ras-transfected COScells following treatment with two of the tricyclic farnesyl transferaseinhibitors of this invention indicated that they also blocked phenotypicchanges induced by expression of oncogenic Ras. Cells expressingoncogenicRas-CVLS or Ras-CVLL overgrew the monolayer and formed densefoci of cells. The compound of Example 1 inhibited the morphologicalchanges induced by Ras-CVLS in a dose-dependent manner over theconcentration range of 2 to 20 μg/mL. The compound of Example 1 hadlittle effect at 0.2 or 0.5 μg/mL. Importantly, 20 μg/mL of the compoundof Example 1 did not prevent the morphological changes induced byRas-CVLL.

These results provide evidence for specific inhibition of farnesylprotein transferase, but not geranylgeranyl transferase I, by compoundsof this invention in intact cells and indicate their potential to blockcellular transformation by activated Ras oncogenes.

3. Cell-Based:

Cell Mat Assay

Tricyclic farnesyl protein transferase inhibitors of this invention alsoinhibited the growth of Ras-transformed tumor cells in the Mat assaywithout displaying cytotoxic activity against the normal monolayer.

In Vivo Anti-Tumor Studies:

Tumor cells (5×10⁵ to 8×10⁶ of M27 (mouse Lewis lung carcinoma), A431(human epidermal carcinoma) or SW620 (human colon adenocarcinoma lymphnode metastasis!)) are innoculated subcutaneously into the flank of 5-6week old athymic nu/nu female mice. For the C-f-1 (mouse fibroblasttransformed with c-fos oncogene) tumor model, 2 mm³ tumor fragments aretransplanted subcutaneously into the flank of 5-6 week old athymic nu/nufemale mice. Tumor bearing animals are selected and randomized when thetumors are established. Animals are treated with vehicle (betacyclodextran for i.p. or corn oil for p.o.) only or compounds in vehicletwice a day (BID) for 5 (1-5), 6 (1-6), or 7 (1-7) days per week for 2(×2) or 4 (×4) weeks. The percent inhibition of tumor growth relative tovehicle controls are determined by tumor measurements. The results arereported in Table 18.

                  TABLE 18                                                        ______________________________________                                        In-Vivo Anti-Tumor Results                                                    s.c.   Route &  Ex     Ex   Ex   Ex   Ex   Ex   Ex                            Tumor  Schedule 2      1    3    7    78   79   75                            ______________________________________                                        M27    po, BID, 61.2   --   27.3 58.2 --   --   --                                   1-7, x4                                                                A431   ip, BID, --     20.5 0    0    --   --   --                                   1-5, x4                                                                A431   po, BID  45.6   --   8    29.1 --   --   --                                   1-5, x4                                                                A431   po, BID, 36.5   --   26   --   --   --   --                                   1-5, x4                                                                A431   po, BID, --     --   --   --   31   0    34.5                                 1-6, x4                                                                C-f-1  ip, BID, 8      0    8    39.7 --   --   --                                   1-5, x2                                                                C-f-1  po, BID, 9.6    --   0    39.3 --   --   --                                   1-5, x4                                                                C-f-1  po, BID, --     --   --   --   26.7 25   20                                   1-5, x4                                                                SW-    ip, BID, 0      0    27   19.6 --   --   --                            620    1-5, x4                                                                SW-    po, BID, 46.1   0    15.8 48.6 --   --   --                            620    1-5, x2                                                                SW-    po, BID, 33.5   --   --   0    --   --   --                            620    1-5, x4                                                                SW-    po, BID, --     --   --   --   59.6 26.7 43.4                          620    1-5, x4                                                                ______________________________________                                    

Additional in-vivo anti-tumor results are reported in Table 19. In Table23, LOX is a human melanoma cell line, and the schedule "10/wk, ×4", forexample, means 10 times per week (twice a day Monday to Friday) for 4weeks.

                  TABLE 19                                                        ______________________________________                                        In-Vivo Anti-Tumor Results                                                    Example                              Average                                  of                Dose      Route &  % Tumor                                  Structure Tumor   (MPK)     Schedule Inhibiton                                ______________________________________                                        Ex. 2     SW620   100       ip, 10/wk, x2                                                                          0                                                  SW620   100       po, 10/wk, x2                                                                          0                                                  SW620   100       po, 10/wk, x4                                                                          1                                                  M27     100       po, 14/wk, x4                                                                          45                                       Ex. 4     SW620   100       po, 10/wk, x4                                                                          2                                        Ex.7      SW620   100       po, 10wk, x2                                                                           13                                                 SW620   100       po, 10/wk, x4                                                                          0                                                  M27     100       po, 14/wk, x4                                                                          40                                       Ex. 45    SW620   100       po, 10/wk, x4                                                                          0                                                  SW620   100       po, 10/wk, x4                                                                          19                                                 M27     100       po, 10/wk, x3                                                                          0                                        Ex. 47    SW820   100       po, 10/wk, x4                                                                          0                                                  SW620   100       po, 10/wk, x4                                                                          30                                                 M27     100       po, 10/wk, x3                                                                          19                                       Ex. 49    SW620   100       po, 10/wk, x4                                                                          0                                                  SW620   100       po, 10/wk, x4                                                                          27                                                 M27     100       po, 10/wk, x3                                                                          30                                       Ex. 75    SW620   100       po, 10/wk, x4                                                                          26                                                 SW620   100       po, 10/wk, x4                                                                          4                                                  SW620   100       po, 10/wk, x4                                                                          54                                                 SW620   100       po, 10/wk, x4                                                                          7                                                  M27     100       po, 10/wk, x4                                                                          0                                        Ex. 82    SW620   100       po, 10/wk, x4                                                                          25                                                 SW620   100       po, 10/wk, x4                                                                          32                                       Ex. 88    SW620   100       po, 10/wk, x4                                                                          43.25*                                             M27     100       po, 10/wk, x4                                                                          19                                                 SW620   100       po, 10/wk, x4                                                                          38*                                                LOX     100       po, 10/1k, x4                                                                          70                                                 SW620   100       po, 10/wk, x4                                                                          38                                                 SW620   100       po, 10/wk, x4                                                                          37                                                 SW620   50        po, 10/wk, x4                                                                          30                                                 SW620   50        po, 10/wk, x4                                                                          30                                                 SW620   25        po, 10/wk, x4                                                                          4                                                  SW620   25        po, 10/wk, x4                                                                          0                                                  SW620   100       po, 10/wk, x4                                                                          27.4*                                              LOX     100       po, 10/wk, x4                                                                          33                                                 SW620   100       po, 10/wk, x4                                                                          28                                                 SW620   100       po, 10/wk, x4                                                                          38                                       Ex. 127   SW620   100       po, 10/wk, x4                                                                          25                                                 SW620   100       po, 10/wk, x4                                                                          42                                                 M27     100       po, 10/wk, x3                                                                          22                                       Ex. 187 (6.8)                                                                           SW620   100       p6, 10/wk, x4                                                                          11                                                 SW620   100       po, 10/wk, x4                                                                          21                                       Ex. 192   SW620   100       po, 10/wk, x4                                                                          29                                                 SW620   100       po, 10/wk, x4                                                                          40                                       Ex. 287   SW620   100       po, 10/wk, x4                                                                          14                                                 SW620   100       po, 10/wk, x4                                                                          0                                        Ex. 290   SW620   100       po, 10/wk, x4                                                                          41                                                 SW620   100       po, 10/wk, x4                                                                          16                                       Ex. 293   SW620   100       po, 10/wk, x4                                                                          5                                                  SW620   100       po, 10/wk, x4                                                                          47                                       Ex. 301   SW620   100       po, 10/wk, x4                                                                          16                                                 SW620   100       po, 10/wk, x4                                                                          0                                        Ex. 82A   SW620   100       po, 10/wk, x4                                                                          27                                                 SW620   100       po, 10/wk, x4                                                                          26                                       Ex. 342   SW620   100       po, 10/wk, x4                                                                          39                                                 SW620   100       po, 10/wk, x4                                                                          31                                       5.21      SW620   100       po, 10/wk, x4                                                                          19                                                 SW620   100       po, 10/wk, x4                                                                          17                                                 M27     100       po, 10/wk, x4                                                                          0                                        5.25      SW620   100       po, 10/wk, x4                                                                          7                                                  SW620   100       po, 10/wk, x4                                                                          36                                       ______________________________________                                         *Average of several results                                              

The compound of Example 342 (Table 19) is: ##STR991##

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 70 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets,powders, cachets and capsules can be used as solid dosage forms suitablefor oral administration.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection.

Liquid form preparations may also include solutions for intranasaladministration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in unit dosage form. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component, e.g., an effectiveamount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 0.1 mg to 1000 mg, more preferably fromabout 1 mg. to 300 mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage for a particular situation is withinthe skill of the art. Generally, treatment is initiated with smallerdosages which are less than the optimum dose of the compound.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. For convenience, thetotal daily dosage may be divided and administered in portions duringthe day if desired.

The amount and frequency of administration of the compounds of theinvention and the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddosage regimen is oral administration of from 10 mg to 2000 mg/daypreferably 10 to 1000 mg/day, in two to four divided doses to blocktumor growth. The compounds are non-toxic when administered within thisdosage range.

The following are examples of pharmaceutical dosage forms which containa compound of the invention. The scope of the invention in itspharmaceutical composition aspect is not to be limited by the examplesprovided.

Pharmaceutical Dosage Form Examples EXAMPLE A Tablets

    ______________________________________                                        No.     Ingredients      mg/tablet                                                                              mg/tablet                                   ______________________________________                                        1.      Active compound  100      5Q0                                         2.      Lactose USP      122      113                                         3.      Corn Starch, Food Grade,                                                                        30       40                                                 as a 10% paste in                                                             Purified Water                                                        4.      Corn Starch, Food Grade                                                                         45       40                                         5.      Magnesium Stearate                                                                              3        7                                                  Total            300      700                                         ______________________________________                                    

Method of Manufacture

Mix Item Nos. 1 and 2 in a suitable mixer for 10-15 minutes. Granulatethe mixture with Item No. 3. Mill the damp granules through a coarsescreen (e.g., 1/4", 0.63 cm) if necessary. Dry the damp granules. Screenthe dried granules if necessary and mix with Item No. 4 and mix for10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress themixture to appropriate size and weigh on a suitable tablet machine.

EXAMPLE B Capsules

    ______________________________________                                        No.    Ingredient      mg/capsule                                                                              mg/capsule                                   ______________________________________                                        1.     Active compound 100       500                                          2.     Lactose USP     106       123                                          3.     Corn Starch, Food Grade                                                                        40        70                                          4.     Magnesium Stearate NF                                                                          7         7                                                  Total           253       700                                          ______________________________________                                    

Method of Manufacture

Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. AddItem No. 4 and mix for 1-3 minutes. Fill the mixture into suitabletwo-piece hard gelatin capsules on a suitable encapsulating machine.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

In addition to the examples provided above, the following compounds wereprepared using the product of Preparative Example 40 and followingsubstantially the same procedures as described for Examples 193, 428,431, 433-A, and 183, as appropriate:

    __________________________________________________________________________                                      Analytical                                  Example No.                                                                         Compound                    Data                                        __________________________________________________________________________    500                                                                                  ##STR992##                 Mass Spec.: MH.sup.+  = 619.15              501                                                                                  ##STR993##                 Mass Spec.: MH.sup.+  = 517                 502                                                                                  ##STR994##                 Mass Spec.: MH.sup.+  = 560                 503                                                                                  ##STR995##                 Mass Spec.: MH.sup.+  = 604.2               504                                                                                  ##STR996##                 Mass Spec.: MH.sup.+  = 532.15              __________________________________________________________________________

EXAMPLE 505 ##STR997##

React the compound of Example 501 with an excess of acetic anhydride inMeOH via standard procedures to form the product compound in 91% yield.Mass Spec.: MH⁺ =559

EXAMPLE 506 ##STR998##

React the compound of Preparative Example 49 with4-(2-bromopyridyl)acetic acid via the substantially the same procedureas described for Example 410 to give the product compound,m.p.=134°-136.1° C.; Mass Spec.: MH⁺ =588

What is claimed is:
 1. A process for producting 3-nitro substitutedcompounds of Formula 1.0h: ##STR999## comprising: reacting one molarequivalent of a compound of Formula 1.0g: ##STR1000## with one molarequivalent of a nitrating reagent, said nitrating reagent beingpreformed by mixing, at cold temperature, equimolar amounts oftetrabutyl ammonium nitrate with trifluoroacetic anhydride;the reactionof said nitrating reagent with said compound of Formula 1.0g takingplace in a solvent selected from the group consisting of: CH₂ Cl₂,CHCl₃, toluene and THF; and said reaction with said nitrating reagentbeing conducted at an initial temperature of 0° C., and said reactiontemperature is thereafter allowed to rise to about 25° C. during thereaction time period to produce the 3-nitro compound of Formula 1.0h;and wherein:a represents N, and the remaining a, b and d groupsrepresent CR¹ or CR² ; each R¹ and each R² is independently selectedfrom H, halo, --CF₃, --OR¹⁰, --COR¹⁰, --SR¹⁰, --S(O)_(t) R¹¹ (wherein tis 0, 1 or 2), --SCN, --N(R¹⁰)₂, --NO₂, --OC(O)R¹⁰, --CO₂ R¹⁰, --OCO₂R¹¹, --CN, --NHC(O)R¹⁰, --NHSO₂ R¹⁰, --CONHR¹⁰, --CONHCH₂ CH₂ OH, NR¹⁰COOR¹¹, --SR¹¹ C(O)OR¹¹, ##STR1001## --SR¹¹ N(R⁷⁵)₂ (wherein each R⁷⁵ isindependently selected from H and --C(O)OR¹¹), benzotriazol-1-yloxy,tetrazol-5-ylthio, or substituted tetrazol-5-ylthio, alkynyl, alkenyl oralkyl, said alkyl or alkenyl group optionally being substituted withhalo, --OR¹⁰ or --CO₂ R¹⁰ ; R³ and R⁴ are the same or different and eachindependently represents H, any of the substituents of R¹ and R², or R³and R⁴ taken together represent a saturated or unsaturated C₅ -C₇ fusedring to the benzene ring; R¹⁰ represents H, alkyl, aryl, or aralkyl; R¹¹represents alkyl or aryl; the dotted line between carbon atoms 5 and 6represents an optional double bond, such that when a double bond ispresent, A and B independently represent --R¹⁰, halo, --OR¹¹, --OCO₂ R¹¹or --OC(O)R¹⁰, and when no double bond is present between carbon atoms 5and 6, A and B each independently represent H₂, --(OR¹¹)₂ ; H and halo,dihalo, alkyl and H, (alkyl)₂, --H and --OC(O)R¹⁰, H and --OR¹⁰, ═O,aryl and H, ═NOR¹⁰ or --O--(CH₂)_(p) --O-- wherein p is 2, 3 or 4; andR⁶⁵ represents H or --OR⁶⁶ wherein R⁶⁶ represents alkyl.
 2. The processof claim 1 wherein R¹ is Cl or H, R² is H, Cl, or Br; R³ and R⁴ areindependently represent H or halo; when the optional bond between carbonatoms 5 and 6 is present, A and B represent H; and when no double bondis present between carbon atoms 5 and 6 A represents H₂ and B representsH₂ or ═O.
 3. The process of claim 2 wherein said aprotic solvent is CH₂Cl₂.
 4. A process for producing 3-nitro compounds of the formula:##STR1002## comprising: reacting one molar equivalent of a compound ofFormula 1.0g: ##STR1003## with one molar equivalent of a nitratingreagent, said nitrating reagent being preformed by mixing, at coldtemperature, equimolar amounts of tetrabutyl ammonium nitrate withtrifluoroacetic anhydride;the reaction of said nitrating reagent withsaid compound of Formula 1.0g taking place in a solvent selected fromthe group consisting of: CH₂ Cl₂, CHCl₃, toluene and THF; and saidreaction with said nitrating reagent being conducted at an initialtemperature of 0° C., and said reaction temperature is thereafterallowed to rise to about 25° C. during the reaction time period toproduce the 3-nitro compound of Formula 1.0h: ##STR1004## hydrolyzingthe compound of Formula 1.0h by dissolving the compound of Formula 1.0hin a sufficient amount of concentrated acid, and heating the resultingmixture to a temperature sufficient to remove the --C(O)R⁶⁵ substituentto produce the compound of Formula 1.0i; and wherein:a represents N, andthe remaining a, b and d groups represent CR¹ or CR² ; each R¹ and eachR² is independently selected from H, halo, --CF₃, --OR¹⁰, --COR¹⁰,--SR¹⁰, --S(O)_(t) R¹¹ (wherein t is 0, 1 or 2), --SCN, --N(R¹⁰)₂,--NO₂, --OC(O)R¹⁰, --CO₂ R¹⁰, --OCO₂ R¹¹, --CN, --NHC(O)R¹⁰, --NHSO₂R¹⁰, --CONHR¹⁰, --CONHCH₂ CH₂ OH, --NR¹⁰ COOR¹¹, --SR¹¹ C(O)OR¹¹,##STR1005## --SR¹¹ N(R⁷⁵)₂ (wherein each R⁷⁵ is independently selectedfrom H and --C(O)OR¹¹), benzotriazol-1-yloxy, tetrazol-5-ylthio, orsubstituted tetrazol-5-ylthio, alkynyl, alkenyl or alkyl, said alkyl oralkenyl group optionally being substituted with halo, --OR¹⁰ or --CO₂R¹⁰ ; R³ and R⁴ are the same or different and each independentlyrepresents H, any of the substituents of R¹ and R², or R³ and R⁴ takentogether represent a saturated or unsaturated C₅ -C₇ fused ring to thebenzene ring; R¹⁰ represents H, alkyl, aryl, or aralkyl; R¹¹ representsalkyl or aryl; the dotted line between carbon atoms 5 and 6 representsan optional double bond, such that when a double bond is present, A andB independently represent --R¹⁰, halo, --OR¹¹, --OCO₂ R¹¹ or --OC(O)R¹⁰,and when no double bond is present between carbon atoms 5 and 6, A and Beach independently represent H₂, --(OR¹¹)₂ ; H and halo, dihalo, alkyland H, (alkyl)₂, --H and --OC(O)R¹⁰, H and --OR¹⁰, ═O, aryl and H,═NOR¹⁰ or --O--(CH₂)_(p) --O-- wherein p is 2, 3 or 4; and R⁶⁵represents H or --OR⁶⁶ wherein R⁶⁶ represents alkyl.
 5. The process ofclaim 4 wherein R¹ is Cl or H; R² is H, Cl or Br; R³ and R⁴ areindependently represent H or halo; when the optional bond between carbonatoms 5 and 6 is present, A and B represent H; and when no double bondis present between carbon atoms 5 and 6 A represents H₂ and B representsH₂ or ═O.
 6. The process of claim 5 wherein said aprotic solvent is CH₂Cl₂.
 7. The process of claim 6 wherein: in hydrolyzing the compound ofFormula 1.0h said concentrated acid is selected from the groupconsisting of: concentrated HCl or aqueous sulfuric acid, and said--C(O)R⁶⁵ substituent is removed by heating to reflux or by heating to atemperature of about 100° C.
 8. A process for producing a compound ofFormula 1.0m: ##STR1006## comprising: reacting one molar equivalent acompound of formula: ##STR1007## with one molar equivalent of anitrating reagent; said nitrating reagent being preformed, by mixing ata cold temperature, equimolar amounts of tetrabutyl ammonium nitratewith trifluoroacetic anhydride;the reaction of said nitrating reagentwith the compound of Formula 1.0k taking place in a solvent selectedfrom the group consisting of: CH₂ Cl₂, CHCl₃, toluene and THF; saidreaction with said nitrating reagent being conducted at an initialtemperature of 0° C., said reaction temperature is thereafter allowed torise to about 25° C. during the reaction time period to produce the3-nitro compound of Formula 1.0j: ##STR1008## reducing said compound ofFormula 1.0j with a suitable reducing agent in a suitable solvent at asuitable temperature to allow the reaction to proceed at a reasonablerate; reacting the resulting hydroxy product with a chlorinating agentin a suitable organic solvent at a suitable temperature to allow thereaction to proceed at a reasonable rate to produce a compound ofFormula 1.0n: ##STR1009## reacting said compound of Formula 1.0n with acompound of the formula: ##STR1010## in a suitable organic solventcontaining a suitable base at a suitable temperature to allow thereaction to proceed at a reasonable rate to produce the compounds ofFormula 1.0m; wherein:a, and the remaining a, b and d groups representCR¹ or CR² ; or each R¹ and each R² is independently selected from H,halo, --CF₃, --OR¹⁰, --COR¹⁰, --SR¹⁰, --S(O)_(t) R¹¹ (wherein t is 0, 1or 2), --SCN, --N(R¹⁰)₂, --NO₂, --OC(O)R¹⁰, --CO₂ R¹⁰, --OCO₂ R¹¹, --CN,--NHC(O)R¹⁰, --NHSO₂ R¹⁰, --CONHR¹⁰, --CONHCH₂ CH₂ OH, --NR¹⁰ COOR¹¹,--SR¹¹ C(O)OR¹¹, ##STR1011## --SR¹¹ N(R⁷⁵)₂ (wherein each R⁷⁵ isindependently selected from H and --C(O)OR¹¹), benzotriazol-1-yloxy,tetrazol-5-ylthio, or substituted tetrazol-5-ylthio, alkynyl, alkenyl oralkyl, said alkyl or alkenyl group optionally being substituted withhalo, --OR¹⁰ or --CO₂ R¹⁰ ; R³ and R⁴ are the same or different and eachindependently represents H, any of the substituents of R¹ and R², or R³and R⁴ taken together represent a saturated or unsaturated C₅ -C₇ fusedring to the benzene ring; R¹⁰ represents H, alkyl, aryl, or aralkyl; R¹¹represents alkyl or aryl; the dotted line between carbon atoms 5 and 6represents an optional double bond, such that when a double bond ispresent, A and B independently represent --R¹⁰, halo, --OR¹¹, --OCO₂ R¹¹or --OC(O)R¹⁰, and when no double bond is present between carbon atoms 5and 6, A and B each indendently represent H₂, --(OR¹¹)₂, H and halo,dihalo, alkyl and H, (alkyl)₂, --H and --OC(O)R¹⁰, H and --OR¹⁰, ═O,aryl and H, ═NOR¹⁰ or --O--(CH₂)_(p) --O-- wherein p is 2, 3 or 4; andR⁶⁸ is H or --COOR^(a) wherein R_(a) is a C₁ to C₃ alkyl group.
 9. Theprocess of claim 8 wherein R¹ is Cl or H; R² is H, Cl or Br; R³ and R⁴are independently represent H or halo; when the optional bond betweencarbon atoms 5 and 6 is present, A and B represent H; and when no doublebond is present between carbon atoms 5 and 6 A represents H₂ and Brepresents H₂ or ═O.
 10. The process of claim 8 wherein for reducingsaid compound of Formula 1.0j said reducing agent is sodium borohydride,said solvent is selected from the group consisting of: ethanol andmethanol, and said temperature is 0° to about 25° C.
 11. The process ofclaim 8 wherein in the reaction to produce the compound of Formula 1.0n,said chlorinating agent is thionyl chloride, said organic solvent isselected from the group consisting of benzene, toluene and pyridine, andsaid temperature is about -20° to about 20° C.
 12. The process of claim8 wherein in the reaction of the compound of Formula 1.0n with##STR1012## said organic solvent is selected from the group consistingof: THF and toluene, said base is selected from the group consisting of:triethylamine and N-methylmorpholine, and said temperature is 25° toabout 120° C.
 13. The process of claim 8 wherein said aprotic solvent isCH₂ Cl₂ in the reaction of the compound of Formula 1.0k with saidnitrating reagent.
 14. The process of claim 8 wherein: (a) in thereaction of said nitrating agent said aprotic solvent is CH₂ Cl₂ ; (b)for reducing said compound of Formula 1.0j said reducing agent is sodiumborohydride, said solvent is selected from the group consisting of:ethanol and methanol, and said temperature is 0° to about 25° C.; (c) inthe reaction to produce the compound of Formula 1.0n, said chlorinatingagent is thionyl chloride, said organic solvent is selected from thegroup consisting of benzene, toluene and pyridine, and said temperatureis about -20° to about 20° C.; (d) in the reaction of the compound ofFormula 1.0n with ##STR1013## said organic solvent is selected from thegroup consisting of: THF and toluene, said base is selected from thegroup consisting of: triethylamine and N-methylmorpholine, and saidtemperature is 25° to about 120° C.; and (e) R¹ is Cl or H, R² is H, Clor Br; R³ and R⁴ are independently represent H or halo; when theoptional bond between carbon atoms 5 and 6 is present A and B representH; and when no double bond is present between carbon atoms 5 and 6 Arepresents H₂ and B represents H₂ or ═O.
 15. A process for producing3-nitro substituted compounds of the formula: ##STR1014## comprising:reacting one molar equivalent of a compound of Formula 1.0g: ##STR1015##with one molar equivalent of a nitrating reagent, said nitrating reagentbeing preformed by mixing, at cold temperature, equimolar amounts oftetrabutyl ammonium nitrate with trifluoroacetic anhydride;the reactionof said nitrating reagent with said compound of Formula 1.0g takingplace in CH₂ Cl₂ ; and said reaction with said nitrating reagent beingconducted at an initial temperature of 0° C., and said reactiontemperature is thereafter allowed to rise to about 25° C. during thereaction time period to produce the 3-nitro compound of Formula 1.0h;and wherein:R⁶⁵ represents H or --OR⁶⁶ wherein R⁶⁶ represents alkyl. 16.The process of claim 15 wherein R⁶⁵ represents --OR⁶⁶ and R⁶⁶ represents--C₂ H₅.
 17. The process of claim 16 wherein the compound ##STR1016## isproduced from the compound ##STR1017##
 18. The process of claim 16wherein the compound ##STR1018## is produced from the compound##STR1019##
 19. A process for producing 3-nitro substituted compounds ofFormula 1.0h: ##STR1020## comprising: reacting one molar equivalent of acompound of Formula 1.0g: ##STR1021## with one molar equivalent of anitrating reagent, said nitrating reagent being preformed by mixing, atcold temperature, equimolar amounts of tetrabutyl ammonium nitrate withtrifluoroacetic anhydride;the reaction of said nitrating reagent withsaid compound of Formula 1.0g taking place in a solvent selected fromthe group consisting of: CH₂ Cl₂, CHCl₃, toluene and THF; and saidreaction with said nitrating reagent being conducted at an initialtemperature of 0° C., and said reaction temperature is thereafterallowed to rise to about 25° C. during the reaction time period toproduce the 3-nitro compound of Formula 1.0h; and wherein:a representsN, and the remaining a, b and d groups represent CR¹ or CR² ; each R¹and each R² is independently selected from H, halo, --CF₃, lower alkylor benzotriazol-1-yloxy; R³ and R⁴ are the same or different and eachindependently represents H, halo, --CF₃, --OR¹⁰ or alkyl; R¹⁰ representsH, alkyl, aryl, or aralkyl; the dotted line between carbon atoms 5 and 6represents an optional double bond, such that when a double bond ispresent, A and B independently represent H, lower alkyl, or alkyloxy;and when no double bond is present between carbon atoms 5 and 6, A and Beach independently represent H₂, --H and --OH, or ═O; and R⁶⁵ representsH or --OR⁶⁶ wherein R⁶⁶ represents alkyl.
 20. The process of claim 19wherein when the optional bond between carbon atoms 5 and 6 is present,A and B represent H; and when no double bond is present between carbonatoms 5 and 6 A represents H₂ and B represents H₂ or ═O.
 21. The processof claim 20 wherein the solvent is CH₂ Cl₂.
 22. The process of claim 21wherein R¹ is Cl or H; R² is H, Cl or Br; R³ and R⁴ are independentlyrepresent H or halo.